@article {pmid41886893,
year = {2026},
author = {Wang, M and Zhang, B and Guo, R and Wang, H and Wu, D and Peng, X and Guo, H and Duan, J and Yang, W and Ren, P and Zhang, S},
title = {Restoration of autophagy-lysosomal function via transcranial focused ultrasound stimulation ameliorates β-amyloid pathology and cognitive deficits in an Alzheimer's disease model.},
journal = {Ultrasonics},
volume = {165},
number = {},
pages = {108075},
doi = {10.1016/j.ultras.2026.108075},
pmid = {41886893},
issn = {1874-9968},
abstract = {Transcranial focused ultrasound (FUS) is a non-invasive neuromodulation technique that regulates intracellular functions and treats brain disorders. In Alzheimer's disease (AD), impaired autophagy-lysosomal pathway (ALP) function leads to the accumulation of β-amyloid (Aβ). However, the potential of FUS alone to alleviate AD pathology by restoring ALP function remains unexplored. In this study, sixteen male transgenic mice with five familial Alzheimer's disease mutations (5×FAD) received bilateral FUS targeting the hippocampus and were compared with sixteen age-matched untreated male 5×FAD mice. Cognitive function was evaluated using behavioral tests, and Aβ pathology was analyzed by immunofluorescence. RNA sequencing, western blotting, and electron microscopy were employed to assess the effects of FUS on the ALP. The results indicated that FUS reduced Aβ deposition and ameliorated cognitive deficits. Compared with the AD group, FUS treatment significantly reduced escape latency by 40.9% (p = 0.010), increased the novel object recognition index by 38.2% (p = 0.016), and increased spontaneous alternation by 18.2% (p = 0.009). Critically, FUS enhanced lysosomal biogenesis and improved autophagosome-lysosome fusion, increasing colocalization efficiency from 28.07 ± 3.73% to 53.22 ± 4.85% in the cortex (p = 0.009) and from 31.95 ± 3.65% to 48.00 ± 2.18% in the hippocampus (p = 0.026). It also promoted the nuclear translocation of transcription factor EB (TFEB). Moreover, the ALP antagonist chloroquine (CQ) suppressed the beneficial effects of FUS, indicating that FUS exerts therapeutic effects in an ALP-dependent manner. Our findings demonstrate that restoring ALP via FUS is a crucial mechanism for mitigating Aβ pathology.},
}

@article {pmid41889233,
year = {2026},
author = {Santos, LRC and de Almeida, JNB and Frias, CC and Almeida, WP and Maistro, EL},
title = {Evaluation of DNA/Chromosome Integrity and Cell Death in Human Metabolically Noncompetent and Competent Cells Exposed to N'-(3,5-Difluorobenzylidene)Pyridine-4-Carbohydrazide.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70171},
pmid = {41889233},
issn = {1099-1263},
support = {Finance code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 303604/2021-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Universidade Estadual Paulista/ ; },
abstract = {The N-acylhydrazone scaffold is recognized as a privileged structure for the design of bioactive substances with increasing applications in medicinal chemistry research. Ensuring the safety of newly developed molecules is a critical step for both human health and environmental protection. Accordingly, this study aimed to evaluate the cytotoxic and genotoxic properties of N'-(3,5-difluorobenzylidene)pyridine-4-carbohydrazide in two cellular models: nonmetabolizing leukocytes and metabolically active hepatic cells (HepG2/C3A). The resazurin-based cytotoxicity analysis, performed with concentrations between 1 and 600 μg/mL, indicated that only the uppermost concentration caused a marked decrease in viability of both cell populations after 48 h of incubation. Regarding genotoxicity at 50, 100, and 200 μg/mL concentrations, no DNA damage was detected in the comet assay, but in the micronucleus test, a significant increase in chromosome alterations in leukocytes at 200 μg/mL concentration was detected, with a decrease in cell proliferation in both cell types. The data indicate that, at the concentrations where the biological effects of acylhydrazone were previously observed, the substance appeared to be safe, but at higher concentrations and/or during chronic exposure, caution and further studies are needed.},
}

@article {pmid41889929,
year = {2026},
author = {Shi, Y and Rozen, SD and Swint, JT and McRoberts, WA and McCurry, SN and Salinas, R and Moffett, EG and Pollock, CM and Goldstein, LR and Katzev, SS and Carter, ME and Bloom, GS and Güler, AD},
title = {LiFE, a multimodal circadian intervention, improves sleep, glycemic control, and recognition memory.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.12.711428},
pmid = {41889929},
issn = {2692-8205},
abstract = {In mammals, sleep is regulated by the central circadian system, which responds to environmental timing cues including light, exercise and availability of food. In this study, we developed a light-, food-, and exercise-based daily lifestyle intervention (LiFE) that combines the effects of multiple circadian entrainment cues on central clock function, ultimately strengthening central clock rhythms. In wild-type (WT) mice, LiFE consolidated nocturnal activity, enhanced suprachiasmatic nucleus rhythmicity, and increased sleep time. Despite comparable caloric intake to control conditions, LiFE lowered baseline blood glucose, reduced glycemic variability, and improved glucose tolerance. We found long-term LiFE treatment improved recognition memory in WT mice. Sleep and circadian disruption are commonly observed in patients with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. We applied long-term LiFE treatment in two AD mouse models (5xFAD and 5xFAD/PS19). Alongside a subtle reduction in AD histopathology, LiFE produced near-significant trends toward improved motor performance and recognition memory. Together, these findings support multimodal circadian chronotherapy as a non-pharmacological approach in which integrated light, feeding, and exercise entrainment promotes sleep and metabolic health.},
}

@article {pmid41890202,
year = {2026},
author = {Zhu, T and Cai, L and Hu, L and Yang, D and Li, M and Quan, F and Lu, C and Liu, S and Cui, J},
title = {Cognitive improvement by non-pharmacological electrical stimulation modalities in mild cognitive impairment: a protocol for systematic review and network meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1752516},
pmid = {41890202},
issn = {1663-4365},
abstract = {OBJECTIVE: Mild cognitive impairment, characterized by progressive cognitive decline, represents a prevalent transitional state among the global aging population and demonstrates high conversion rates to Alzheimer's disease, establishing itself as a critical window for preventive interventions against AD. Although growing evidence supports the efficacy of various non-pharmacological therapies in enhancing cognitive function, their comparative effectiveness remains insufficiently elucidated. This study aims to analyze the efficacy and safety of different electrical stimulation modalities in treating MCI patients, quantitatively compare the therapeutic benefits across multiple interventions, and provide evidence-based recommendations to facilitate informed clinical decision-making.

METHODS: We will systematically search 13 databases. All relevant studies published from inception until November 1, 2025, will be retrieved. Two reviewers will independently assess the risk of bias for all included studies using the revised Cochrane Risk of Bias tool (RoB 2). The primary outcome will be the Montreal Cognitive Assessment score to evaluate changes in cognitive function. Secondary outcomes will include neuropsychological assessments related to cognition, such as the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), as well as the modified Barthel Index for activities of daily living and the patient-reported Pittsburgh Sleep Quality Index. Data synthesis will be performed using Stata software, employing a random-effects network meta-analysis model to compare the efficacy and safety of non-pharmacological electrical stimulation therapies. The surface under the cumulative ranking curve (SUCRA) will be used to estimate the probability of intervention hierarchies. The strength of evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations framework.

CONCLUSION: This study will synthesize evidence from multiple studies on various electrical stimulation therapies for improving cognitive function in patients with mild cognitive impairment, thereby providing a diverse body of evidence to support clinical decision-making by physicians and optimization of treatment strategies for patients.

STUDY PROTOCOLS REGISTRATION: [https://www.crd.york.ac.uk/prospero/], identifier [CRD420251184505].},
}

@article {pmid41891120,
year = {2026},
author = {Grande, I and Schmidt, SN and Reines, E and Christensen, MC},
title = {Vortioxetine in Subgroups of Patients with Major Depressive Disorder and Early-Stage Dementia: Further Results from the MEMORY Study.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {549106},
pmid = {41891120},
issn = {1176-6328},
abstract = {BACKGROUND: Depression and dementia are common in older adults; however, many antidepressants have limited effectiveness in patients with major depressive disorder (MDD) comorbid with dementia. In the MEMORY study (NCT04294654), significant improvements in depressive symptom severity, cognitive performance, overall functioning, and health-related quality of life were seen in patients with MDD and early-stage dementia during treatment with vortioxetine. This subgroup analysis was undertaken to further explore the effectiveness of vortioxetine in this patient population.

METHODS: MEMORY was a multinational, open-label, Phase IV study. Patients (n = 82) aged 55-85 years with MDD and early-stage dementia were treated with vortioxetine (5-20 mg/day) for 12 weeks. This was a post-hoc analysis for four key subgroups of patients in this study: (i) those with Alzheimer's disease (n = 35), (ii) those with mixed-type dementia (n = 22), (iii) those receiving concomitant drugs for dementia (n = 34), and (iv) those with severe depression (Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥30) at baseline (n = 42).

RESULTS: Significant improvement in depressive symptom severity was seen in all patient subgroups from week 1 onwards (P < 0.05). At week 12, the mean change from baseline ranged from approximately -12 to -14 for MADRS total score (P < 0.0001), -6 to -8 for MADRS anhedonia subscore (P < 0.0001), and +3 to +6 for Digit Symbol Substitution Test score (P < 0.05). Improvements in verbal memory, ability to perform activities of daily living, health-related quality of life, and overall disease severity were also observed in all patient subgroups.

CONCLUSION: Our findings provide further support for the effectiveness and tolerability of vortioxetine in patients with MDD and early-stage dementia. Clinically significant improvement in depressive symptoms, cognitive performance, and health-related quality of life during treatment with vortioxetine was observed in patients with Alzheimer's disease, those with mixed-type dementia, patients receiving concomitant treatment with drugs for dementia, and those with severe depression.},
}

@article {pmid41892131,
year = {2026},
author = {Kasabov, NK and Yang, A and Wang, Z and Abouhassan, I and Kassabova, A and Lappas, T},
title = {eXCube2: Explainable Brain-Inspired Spiking Neural Network Framework for Emotion Recognition from Audio, Visual and Multimodal Audio-Visual Data.},
journal = {Biomimetics (Basel, Switzerland)},
volume = {11},
number = {3},
pages = {},
doi = {10.3390/biomimetics11030208},
pmid = {41892131},
issn = {2313-7673},
abstract = {This paper introduces a biomimetic framework and novel brain-inspired AI (BIAI) models based on spiking neural networks (SNNs) for emotional state recognition from audio (speech), visual (face), and integrated multimodal audio-visual data. The developed framework, named eXCube2, uses a three-dimensional SNN architecture NeuCube that is spatially structured according to a human brain template. The BIAI models developed in eXCube2 are trainable on spatio- and spectro-temporal data using brain-inspired learning rules. Such models are explainable in terms of revealing patterns in data and are adaptable to new data. The eXCube2 models are implemented as software systems and tested on speech and video data of subjects expressing emotional states. The use of a brain template for the SNN structure enables brain-inspired tonotopic and stereo mapping of audio inputs, topographic mapping of visual data, and the combined use of both modalities. This novel approach brings AI-based emotional state recognition closer to human perception, provides a better explainability and adaptability than existing AI systems. It also results in a higher or competitive accuracy, even though this was not the main goal here. This is demonstrated through experiments on benchmark datasets, achieving classification accuracy above 80% on single-modality data and 88.9% when multimodal audio-visual data are used, and a "don't know" output is introduced. The paper further discusses possible applications of the proposed eXCube2 framework to other audio, visual, and audio-visual data for solving challenging problems, such as recognizing emotional states of people from different origins; brain state diagnosis (e.g., Parkinson's disease, Alzheimer's disease, ADHD, dementia); measuring response to treatment over time; evaluating satisfaction responses from online clients; cognitive robotics; human-robot interaction; chatbots; and interactive computer games. The SNN-based implementation of BIAI also enables the use of neuromorphic chips and platforms, leading to reduced power consumption, smaller device size, higher performance accuracy, and improved adaptability and explainability. This research shows a step toward building brain-inspired AI systems.},
}

@article {pmid41892340,
year = {2026},
author = {Cohen, BM and Koh, E and Levental, KR and Levental, I and Sonntag, KC},
title = {Inherent Lipid Composition Abnormalities in Astrocytes Associated with Late-Onset Alzheimer's Disease (LOAD).},
journal = {Cells},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/cells15060549},
pmid = {41892340},
issn = {2073-4409},
support = {N/A//Steele Fund SUNDRY/ ; R35GM134949/GM/NIGMS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; Lipidomics ; Fatty Acids/metabolism ; *Lipid Metabolism ; Mitochondria/metabolism ; *Lipids/chemistry ; Aged ; Male ; Cholesterol Esters/metabolism ; },
abstract = {Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Astrocytes/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism
Lipidomics
Fatty Acids/metabolism
*Lipid Metabolism
Mitochondria/metabolism
*Lipids/chemistry
Aged
Male
Cholesterol Esters/metabolism

@article {pmid41892608,
year = {2026},
author = {Zhang, T and Sun, F and Stang, A and Ayoub, G},
title = {Peripheral Sensory Stimulation for Long-Term Improvement in Mild Cognitive Decline: A Prospective Interventional Study.},
journal = {Brain sciences},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/brainsci16030265},
pmid = {41892608},
issn = {2076-3425},
support = {grant in aid//Nova Palm Foundation/ ; },
abstract = {BACKGROUND: Despite recent breakthroughs in pharmacological treatment for Alzheimer's disease, high costs and the complex procedure to monitor safety have limited access for many patients. Less invasive and more accessible non-pharmacological therapies that support neuroplasticity and slow cognitive decline are needed. Processing Inner Strength Toward Actualization (PISTA) stimulation applies structured tactile input to promote cortical-subcortical activation. This study evaluated the long-term effects of PISTA on cognition and pain in older adults with mild cognitive impairment or early dementia.

METHODS: This single-arm, prospective trial enrolled 100 outpatients aged 47-70 years at outset (50 women, 50 men) with no control group. Participants received clinician-supervised PISTA stimulation three times weekly for 48 months. Each 30 min session delivered rhythmic tactile input calibrated to individual sensory thresholds. Cognitive performance was assessed monthly using the Mini-Mental State Examination (MMSE). Perceived pain was measured monthly with the Numeric Pain Rating Scale. Outcomes were analyzed using ANCOVA, adjusting for age, sex, and baseline cognitive status.

RESULTS: Cognitive scores improved significantly across all age strata, with a mean annual MMSE increase of 0.75 points (95% CI: 0.26-1.21; p < 0.0025). Pain intensity decreased in parallel (mean reduction: 0.56 points; 95% CI: 0.34-0.78; p < 0.001). Improvements in cognition and pain were moderately correlated (r = 0.38). The greatest combined benefits occurred in participants aged 55-62 years. No serious adverse events were observed during the 48-month trial.

CONCLUSIONS: PISTA stimulation produced sustained improvement in cognition and reduced perceived pain, supporting its promising role as a safe, non-invasive adjunct for neurodegenerative cognitive decline. These findings suggest peripheral sensory activation as a promising driver of functional neuroplasticity and warrant verification in randomized, controlled trials.},
}

@article {pmid41893324,
year = {2026},
author = {Bientinesi, E and Vignoli, A and Ristori, S and Salobehaj, M and Bertoni, G and Monti, D and Tenori, L},
title = {An NMR-Based Protocol for Profiling the Endo- and Exo-Metabolomes in Aβ1-42 Treated Human Astrocytes from Healthy and Alzheimer's Disease Donors.},
journal = {Metabolites},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/metabo16030173},
pmid = {41893324},
issn = {2218-1989},
support = {M4C2 Investment 1.3 - Research Program PE8 Project Age-It: "Ageing Well in an Ageing Society" (CUP B83C22004800006)//Ministero dell'università e della ricerca/ ; },
abstract = {Background/Objectives: Astrocytes play a critical role in maintaining brain homeostasis and are increasingly recognized as active contributors to neurodegenerative processes. Metabolic dysfunction in astrocytes has been implicated in the onset and progression of Alzheimer's disease (AD), yet the underlying metabolic alterations remain poorly characterized. Methods: We used an optimized protocol for untargeted metabolomic profiling of both intracellular and extracellular compartments of primary human astrocytes derived from AD patients and healthy subjects (HS) using [1]H nuclear magnetic resonance (NMR) spectroscopy. Cells were treated with oligomeric Aβ1-42 to model pathological conditions. Results: Aβ1-42 treatment induced intracellular metabolic alterations in both AD and HS astrocytes, including a consistent reduction in phosphocreatine, potentially indicating impaired energy-buffering capacity. Notably, a decrease in β-alanine was observed only in AD astrocytes, suggesting alterations in carnosine-related antioxidant defence. Analysis of conditioned media revealed differential responses between groups: AD astrocytes showed increased extracellular levels of 2-oxoglutarate, citrate, and glycine, whereas HS astrocytes exhibited reduced extracellular levels of leucine and isoleucine, suggesting distinct adaptive metabolic responses to Aβ-induced stress. However, none of these differences remained statistically significant after correction for multiple testing. Conclusions: These findings suggest that NMR-based metabolomics can detect subtle metabolic shifts in human astrocyte models of AD and HS exposed to amiloidogenic challenge. Given the limited sample size and the exploratory design adopted, the results should be interpreted as preliminary and require validation in larger, better-matched cohorts. Nevertheless, this study provides a methodological framework and generates biologically plausible hypotheses regarding astrocyte metabolic responses relevant to AD pathophysiology.},
}

@article {pmid41893345,
year = {2026},
author = {Yang, D and Guo, W and Guo, L},
title = {Exercise Reprograms the Spatial Function of Phosphoglycerate Dehydrogenase of a Pathogenic Nuclear Transcription Factor (PHGDH): A Narrative Review.},
journal = {Metabolites},
volume = {16},
number = {3},
pages = {},
doi = {10.3390/metabo16030196},
pmid = {41893345},
issn = {2218-1989},
abstract = {Background: Alzheimer's disease (AD) represents a significant therapeutic challenge, largely attributed to the complex interplay of genetic and non-genetic mechanisms. Among the latter, metabolic dysregulation has emerged as a critical factor influencing disease progression. This study proposes a paradigm shift in our understanding of the role of phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, which, under pathological conditions associated with AD, transitions from a protective role to a pathogenic influence through alterations in its cellular localization and function. Methods: To elucidate the impact of exercise on PHGDH dynamics, a narrative review methodology was employed. We conducted comprehensive searches across bibliographic databases, including PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles that detail the relationship between exercise, PHGDH activity, and AD-related neuroinflammation. The review was structured around specific inclusion criteria, which prioritized studies elucidating the mechanisms underlying PHGDH's dual role in AD pathology and the influence of exercise on this process. Results: Our findings reveal that under AD-associated stress, PHGDH translocates to the nucleus, facilitating the activation of pro-inflammatory genes such as IKKα and HMGB1, while simultaneously suppressing autophagy and enhancing amyloid beta (Aβ) deposition. However, exercise induces the release of the myokine irisin, which inhibits PHGDH nuclear translocation through AMPK/PGC-1α signaling pathways. Additionally, peripheral effects of exercise are observed in hepatic Kupffer cells, where exercise attenuates PHGDH activity, leading to reduced systemic IL-1β release and neuroinflammation. Conclusions: This study underscores the potential of exercise as a precision intervention in AD management, highlighting its capacity to modulate PHGDH activity and mitigate neuroinflammatory processes. The therapeutic implications of these findings are profound, paving the way for novel diagnostic tools, such as PET probes for assessing PHGDH compartmentalization, and promoting a synergistic approach to "exercise-pharmacotherapy" in the treatment of Alzheimer's disease. Future research should aim to further delineate the mechanisms by which exercise influences metabolic pathways in the context of neurodegeneration.},
}

@article {pmid41893846,
year = {2026},
author = {Lin, Z and Sun, R and Ross, JS and Lau, K and Stumpf, S and Chen, X},
title = {Racial and Ethnic Reporting and Representation in US Alzheimer Clinical Trials: A Systematic Review.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e262427},
doi = {10.1001/jamanetworkopen.2026.2427},
pmid = {41893846},
issn = {2574-3805},
mesh = {Humans ; *Alzheimer Disease/drug therapy/ethnology ; United States ; *Ethnicity/statistics & numerical data ; *Racial Groups/statistics & numerical data ; *Clinical Trials, Phase III as Topic/statistics & numerical data ; Clinical Trials as Topic ; },
abstract = {IMPORTANCE: Alzheimer disease (AD) disproportionately affects racial and ethnic populations underrepresented in US clinical research, raising concerns about the generalizability of AD trial findings and the evaluation of treatment safety and efficacy for populations most affected by AD.

OBJECTIVE: To examine patterns and trends in the reporting and representation of patient race and ethnicity in US-based phase 3 AD clinical trials.

EVIDENCE REVIEW: This systematic review examined US-based phase 3 AD drug trials identified through the Trialtrove trial database between 1997 and 2023. Trials were cross-referenced with peer-reviewed publications, ClinicalTrials.gov, pharmaceutical company reports, and conference abstracts. Completed trials were eligible for inclusion if they were designated as phase 3 drug trials targeting AD and recruited patients exclusively in the US. Primary outcomes included reporting of race and ethnicity, the number of racial and ethnic groups reported, and their representation among trial populations. Secondary outcomes included terminology used, reporting of safety or efficacy differences by race and ethnicity, and discussion of racial and ethnic representation in trial reports. Temporal trends in reporting and representation were assessed. Methodologic quality was evaluated using the Quality Rating Scheme for Studies and Other Evidence. Data collection was completed May 2024.

FINDINGS: Among 88 US-based phase 3 AD clinical trials conducted between 1997 and 2023, 71 (80.7%) had publicly available results, including 52 (59.1%) published in peer-reviewed journals. Nearly half of published trials (35 [49.3%]) did not report patient race or ethnicity. Among published trials, reporting was inconsistent and focused predominantly on White (36 [50.7%]) patients, with substantially fewer trials reporting data on Asian or Pacific Islander (11 [15.5%]), Black (20 [28.2%]), Hispanic (13 [18.3%]), or Native American (2 [2.8%]) patients. Median (IQR) enrollment of White patients was 91.3% (87.3%-93.6%), whereas enrollment of underrepresented patient populations was markedly lower, with median (IQR) enrollment of 0.9% (0.6%-1.6%) for Asian or Pacific Islander, 4.5% (3.6%-6.6%) for Black (ethnicity unspecified), 7.2% (3.7%-9.1%) for Black (non-Hispanic), 5.2% (3.1%-6.6%) for Hispanic, and 0.4% (0%-0.8%) for Native American patients. Few trials (3 of 71 [4.2%]) conducted subgroup analyses by race or ethnicity, and none reported detailed subgroup characteristics or safety or efficacy outcomes by patient race and ethnicity. Reporting practices and representation showed little improvement over time.

CONCLUSIONS AND RELEVANCE: US-based phase 3 AD trials showed substantial gaps in racial and ethnic reporting and representation from 1997 to 2023, limiting the evaluation of treatment safety and efficacy across diverse populations. These findings suggest that stronger reporting standards and more inclusive trial design and recruitment strategies are needed to improve the equity and generalizability of AD trials.},
}

Humans
*Alzheimer Disease/drug therapy/ethnology
United States
*Ethnicity/statistics & numerical data
*Racial Groups/statistics & numerical data
*Clinical Trials, Phase III as Topic/statistics & numerical data
Clinical Trials as Topic

@article {pmid41894159,
year = {2026},
author = {Suemoto, CK and Custodio, N and Aguilar, D and Avila-Funes, JA and Baez, S and Bagnati, PM and Barnes, LL and Brucki, SMD and Calandri, IL and Caramelli, P and Cornejo-Olivas, M and Derio, CD and Ferreira, ST and García, AM and Grinberg, LT and Ibanez, AM and Isasi, R and Josephy-Hernández, SE and Porras, ML and Llibre-Guerra, JJ and Llibre-Rodriguez, JJ and Lourenco, MV and Meza, BMM and Migeot, J and Miranda, JJ and Miranda-Castillo, C and Mummery, CJ and Parodi, JF and Castro, NP and Contreras, RMS and Santamaría-García, H and Slachevsky, A and Souza-Talarico, JN and Surace, EI and Takada, LT and Tsoy, E and Pilalumbo, MU and Zimmer, ER and Fontana, IC and Mahinrad, S and Snyder, HM and Carrillo, MC},
title = {The landscape of dementia research, diagnosis, treatment, and care in Latin America.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71309},
doi = {10.1002/alz.71309},
pmid = {41894159},
issn = {1552-5279},
support = {//Global Brain Health Institute/ ; //ANID/FONDEF/ ; //ANID/Fondecyt/ ; //ANID/Fondap/ ; //NIH D43 Fogarty/ ; //ANID Millennium Science Initiative Program/ ; //National Institute for Health and Care Research/ ; //ANID/PIA/ANILLOS/ ; //Multi-partner Consortium to Expand Dementia Research in Latin America (ReDLat)/ ; //DICYT-USACH/ ; //Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; //National Institute for Translational Neuroscience (INNT-Brazil)/ ; //Agencia Nacional de Investigación y Desarrollo/ ; //Consejo Nacional de Desarrollo Científico y Tecnológico/ ; //Pilot Awards for Global Brain Health Leaders (Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society)/ ; /NH/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Agencia Nacional de Promoción Científica y Tecnológica/ ; //Takeda/ ; //National Institutes of Aging/ ; },
mesh = {Humans ; *Dementia/diagnosis/therapy/epidemiology ; Latin America/epidemiology ; *Biomedical Research ; Congresses as Topic ; },
abstract = {Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep-rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14-15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.},
}

Humans
*Dementia/diagnosis/therapy/epidemiology
Latin America/epidemiology
*Biomedical Research
Congresses as Topic

@article {pmid41894949,
year = {2026},
author = {Brem, AK and Khan, Z and Radermacher, J and Georgiadis, K and Lazarou, I and Grammatikopoulou, M and Pickering, E and Mitterreiter, J and Aakre, JA and Ashton, NJ and Baquero, M and Beser-Robles, M and Braboszcz, C and Brandt, S and Brown, J and Cacciamani, F and Campill, S and Collins, C and Deshpande, P and Diaz, A and Durrleman, S and Engelborghs, S and Ferré-González, L and Frisoni, GB and Gjestsen, MT and Gove, D and Honigberg, L and Huang, B and Hudak, A and Kaushik, S and Letoha, T and Marquardt, G and Mendes, AJ and Müllenborn, M and Paletta, L and de Barros, NP and Pszeida, M and Vik-Mo, AO and Rostamipour, H and Perneczky, R and Rauchmann, BS and Russegger, S and Schirmer, T and Shadmaan, A and Solana, AB and Soria-Frisch, A and Tegethoff, P and Ribbens, A and De Witte, S and van der Giezen, M and Nikolopoulos, S and Corbett, A and Fröhlich, H and Aarsland, D and , },
title = {Screening for Alzheimer's disease in the community using an AI-driven screening platform: design of the PREDICTOM study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100545},
doi = {10.1016/j.tjpad.2026.100545},
pmid = {41894949},
issn = {2426-0266},
abstract = {BACKGROUND: Recent developments in physiological, imaging and digital biomarkers combined with the approval of new disease-modifying drugs against Alzheimer's disease (AD) and diagnostic blood tests provide an opportunity to shift the first diagnostic steps to the home-setting. While these novel biomarkers enable scalable screening and earlier detection and treatment of AD, they require an evaluation of their accuracy, feasibility, and safety in primary care and the community setting.

OBJECTIVES: The aim of PREDICTOM is to develop and test the accuracy of an artificial intelligence (AI) driven screening platform for the risk assessment and early detection of AD to extend the clinical pathway to home-based screening using established and novel biomarkers.

DESIGN/SETTING: PREDICTOM is a European (Norway, UK, Belgium, France, Switzerland, Germany, Spain) observational, prospective cohort study using a cloud-based platform that stores a digitalised journey for each participant and provides a collection of artificial-intelligence (AI) algorithms and tools for risk assessment and early diagnosis and prognosis.

PARTICIPANTS: Cohort 1 consists of 4000 adults aged 50 years or older at risk of developing AD. Cohort 2 consists of 615 participants selected from Cohort 1 based on estimates indicating high (N = 415) or low (N = 200) risk of AD. Data from existing cohorts will guide the analytic strategy of the study.

MEASUREMENTS: Cohort 1 will undergo home-based assessments (Level 1), Cohort 2 will undergo in-clinic assessments (Levels 2 and 3). Level 1 includes at-home screening, collecting digital and physiological data (questionnaires, cognition, hearing, eye-tracking) and biofluids (capillary blood via finger-stick and saliva) for biomarker analysis. Level 2 comprises a more complex biomarker collection, most of which can be completed in primary care, including EEG, MRI, venous blood, microbiome from stool, cognition, hearing, and eye-tracking. Level 3 includes a diagnostic evaluation to confirm or rule out AD pathology using established biomarkers (cerebrospinal fluid, or amyloid PET).

CONCLUSIONS: PREDICTOM will develop AI-driven algorithms for the early detection of AD using biomarkers that can be collected at home or in the community care setting, and evaluate their integration into a well-defined and comprehensive clinical pathway.},
}

@article {pmid41895394,
year = {2026},
author = {Xia, X and Yi, F and Zhang, R and Wu, R and Zhang, X and Zhang, Y and Liu, J and Qin, H and He, B and Duan, Y and Xu, Y and Huang, XF and Yu, Y and Hu, M},
title = {Senolytic therapy ameliorates high-fat diet-induced hippocampal senescence and cognitive decline in mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115745},
doi = {10.1016/j.expneurol.2026.115745},
pmid = {41895394},
issn = {1090-2430},
abstract = {Obesity is a recognized risk factor for cognitive decline and neurodegenerative diseases, including Alzheimer's disease (AD). Obese individuals typically consume high-fat diet (HFD), particularly those rich in palmitate. However, the potential for HFD to induce neurodegeneration and their underlying mechanisms remain poorly understood. In this study, we demonstrate that HFD exposure induced significant deficits in hippocampal-dependent behaviors in mice and decreased synaptic protein expression. Transcriptomic analysis revealed differentially expressed genes in the hippocampus of HFD-fed mice, with enrichment predominantly in senescence-associated pathways. Furthermore, HFD-fed mice exhibited elevated hippocampal senescence markers, including increased SA-β-gal-positive cells, upregulated p16/p21 expression, elevated SASP factors and reduced Lamin B1. Remarkably, a palmitate-enriched diet recapitulated the hippocampal senescence phenotype and cognitive deficits induced by HFD, indicating that palmitate-the principal saturated fatty acid in HFD-served as a key mediator of cellular senescence. Finally, treatment with the senolytic cocktail dasatinib plus quercetin significantly reduced senescent cell burden, suppressed p16 protein expression, and normalized SASP factor levels. This intervention effectively restored cognitive function and synaptic protein expression. This work uncovers a novel HFD-induced cognitive impairment mechanism and suggests potential therapeutic strategies for mitigating obesity-associated neurodegeneration.},
}

@article {pmid41895668,
year = {2026},
author = {Jung, H and Hyun, G and Kim, S and Jeon, Y and Han, KA and Lee, KJ and Ko, J and Um, JW},
title = {Somatostatin-induced modulation of microglial activity contributes to mitigating Alzheimer's disease pathology.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106563},
doi = {10.1016/j.bbi.2026.106563},
pmid = {41895668},
issn = {1090-2139},
abstract = {Somatostatin (SST) is a neuropeptide widely expressed in the central nervous system, known to exert inhibitory effects through activation of G protein-coupled somatostatin receptors (SSTRs). Although its synaptic and network-level functions have been implicated in various neurological disorders, the direct peptidergic actions of SST-particularly on microglia-remain poorly understood. Given that SST levels are reduced in Alzheimer's disease (AD) and microglia predominantly express SSTR2, we hypothesized that SST modulates microglial function both in physiological and AD-related contexts. In this study, we demonstrate that SST treatment enhances phagocytic capacity and suppresses pro-inflammatory cytokine release in cultured microglia. Furthermore, SST overexpression in an AD mouse model reduced microglial density and amyloid-β plaque burden and improved hippocampus-dependent cognitive performance, indicating a protective effect mediated through microglial modulation. Our findings suggest a previously unrecognized role of SST in regulating microglial behavior and highlight the therapeutic potential of targeting the SST-SSTR signaling axis in neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid41895681,
year = {2026},
author = {Iwao, T and Takata, F and Tanaka, Y and Aridome, H and Mizoguchi, J and Dohgu, S},
title = {Docosahexaenoic and eicosapentaenoic acids differentially enhance the blood-brain barrier function via distinct PPAR-dependent upregulation of tight junction proteins in brain endothelial cells.},
journal = {Microvascular research},
volume = {},
number = {},
pages = {104948},
doi = {10.1016/j.mvr.2026.104948},
pmid = {41895681},
issn = {1095-9319},
abstract = {Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are unsaturated omega-3 fatty acids that reduce the risk of Alzheimer's disease and dementia by protecting blood-brain barrier (BBB) function. However, the mechanisms through which DHA and EPA regulate BBB function remain unclear. DHA and EPA act as ligands for the peroxisome proliferator-activated receptor (PPAR), which is a nuclear receptor superfamily member, with three isoforms: α, β, and γ. Tight junctions (TJs) formed between brain endothelial cells play a central role in restricting the paracellular passage of substances across the BBB. In this study, we aimed to investigate whether DHA and EPA regulate TJ protein expression via PPARs. Primary cultured rat brain endothelial cells (RBECs) isolated from Wistar rats were used for in vitro analysis. TJ protein (ZO-1, occludin, and claudin5) and PPARα, β, and γ expression levels in RBECs were measured using western blot analysis. Additionally, to verify PPAR involvement in TJ protein expression regulation, RBECs were treated with DHA or EPA in combination with PPARα, β, or γ inhibitors. The DHA-induced ZO-1 upregulation was suppressed by PPARβ inhibition. Either PPARβ or PPARγ inhibition suppressed the DHA-induced occludin increase, whereas both PPAR inhibitors suppressed the DHA-induced claudin-5 increase. In contrast, the EPA-induced increase in claudin-5 expression was suppressed via PPARγ inhibition. Conclusively, DHA and EPA regulate TJ protein expression via different PPARs in brain endothelial cells, revealing potential targets for the prevention or treatment of neurodegenerative diseases.},
}

@article {pmid41895957,
year = {2026},
author = {Ma, W and Wang, S and Yang, X and Chen, YB and Li, Y and Cui, YL},
title = {Gastrodin and gastrodigenin: advancing neurogenesis in neurological disease management.},
journal = {Food research international (Ottawa, Ont.)},
volume = {232},
number = {},
pages = {118882},
doi = {10.1016/j.foodres.2026.118882},
pmid = {41895957},
issn = {1873-7145},
mesh = {*Benzyl Alcohols/pharmacology/therapeutic use ; *Neurogenesis/drug effects ; *Glucosides/pharmacology/therapeutic use ; Humans ; Animals ; Gastrodia/chemistry ; *Nervous System Diseases/drug therapy ; Neural Stem Cells/drug effects ; },
abstract = {Neurogenesis, the creation of new neurons from neural stem cells (NSCs) in the brain, plays a crucial role in neurological diseases when disrupted. Herbal medicine components, especially those with dual applications in disease treatment and food, like those from Gastrodia elata Blume, have gained attention for their ability to influence neurogenesis. Notably, gastrodin and gastrodigenin from this herb influence neurogenesis and affect conditions like Alzheimer's, depression, stroke, and amnesia. Understanding these processes and mechanisms is essential for addressing neurological disorders. We also discuss gastrodin's potential in aiding peripheral nerve regeneration and its therapeutic effects on neurological diseases through neurogenesis regulation. This review offers insights into gastrodin's therapeutic potential, encouraging further research to boost its efficacy in neurological diseases.},
}

*Benzyl Alcohols/pharmacology/therapeutic use
*Neurogenesis/drug effects
*Glucosides/pharmacology/therapeutic use
Humans
Animals
Gastrodia/chemistry
*Nervous System Diseases/drug therapy
Neural Stem Cells/drug effects

@article {pmid41555522,
year = {2026},
author = {Lahiri, D and Cooper, J and Seixas-Lima, B and Roncero, C and Wellington, C and Cherktow, H},
title = {CAPS Plus: A Clinical Biomarker Scoring System to Predict Aβ Positivity and Facilitate Enrollment in Anti-Amyloid Clinical Trials.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-8},
doi = {10.1017/cjn.2026.10530},
pmid = {41555522},
issn = {0317-1671},
abstract = {BACKGROUND: A critical step toward determining eligibility for experimental and clinical treatment with anti-amyloid therapies in Alzheimer's disease (AD) is to select appropriate subjects having a high likelihood of being Aβ+. We propose a clinical biomarker composite score, named Clinical β-Amyloid Positivity Prediction Score Plus (CAPS Plus), for Aβ+ prediction in people presenting with clinical Alzheimer's syndrome including both prodromal and mild AD.

METHODS: The original CAPS incorporated scores from the neuropsychiatry inventory questionnaire, mini-mental state examination score loss per year and Fazekas score. Plasma p-tau-217, a novel addition to CAPS, was measured using the Simoa HD-X with the AlzPATH p-tau217 Advantage Plus assay. To incorporate p-tau-217 into CAPS Plus, an intra-cohort cut-off (>0.698 pg/ml) for p-tau217 was generated using logistic regression and Yoden's index. CAPS Plus had a maximum score of 5, with those ≥4 indicating a high probability of being Aβ+. The accuracy of CAPS Plus was computed through logistic regression and area under the receiver operating characteristic curve (AUROC) analysis.

RESULTS: Of n = 44 patients, n = 25 (57%) were Aβ+. Plasma p-tau-217 was significantly higher in the Aβ+ subgroup (1.36 vs 0.46 pg/mL, p < 0.0001). The AUROC was 0.89 for a CAPS Plus score of 4 or more, suggesting excellent discrimination and improving the accuracy of the original CAPS (0.86). CAPS Plus has a notably better specificity (89%) than the original CAPS (80%) and p-tau-217 alone (74%).

CONCLUSION: CAPS Plus is potentially a useful screening tool for enrollment in anti-Aβ therapy and clinical trials for AD, specifically addressing people with prodromal and mild AD.},
}

@article {pmid41691301,
year = {2026},
author = {Penny, LK and Arastoo, M and Lofthouse, R and Abdallah, A and Imoesi, PI and Schwab, K and Shiells, H and Melis, V and Riedel, G and Harrington, CR and Wischik, CM and Porter, A and Palliyil, S},
title = {Timing matters: early administration of a high-affinity antibody targeting the tau repeat domain prevents aggregation in a mouse tauopathy model.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41691301},
issn = {1758-9193},
abstract = {INTRODUCTION: Immunotherapy is an attractive proposition for preventing the spread of pathologic tau in Alzheimer’s disease and other tauopathies. Given that tau is heavily truncated in tauopathies, it is hypothesised that directly targeting the repeat domain which forms the core of pathological filaments will improve the likelihood of success. S1D12, a chimeric IgG2a isolated via phage display, recognises 2N4R tau341-353 with high affinity (200 pM) and has previously been shown to prevent tau aggregation and propagation in vitro. We further explored the pharmacokinetics and biodistribution of S1D12 as well as its efficacy in a tauopathy mouse model. We also verified its efficacy in vitro against tau seeding species from multiple human tauopathies.

METHODS: Single dose S1D12 intraperitoneal injections (30 mg/kg) were performed in wild-type mice followed by tissue harvest at multiple time points. For efficacy studies, four-weekly doses followed by four-fortnightly doses of S1D12 (30 mg/kg) or negative control antibody were administered intraperitoneally to Line 66 tau transgenic mice. Two cohorts, beginning from 2 months and 4.5 months of age were utilised. Endpoints included quantification of aggregated tau, seed-competent tau and insoluble phosphorylated tau in brain homogenates, as well as neurofilament light (NfL), tau phosphorylated at Thr-217 (pTau217) and core tau in plasma.

RESULTS: S1D12 was detected in plasma and in brain with a tmax of 24/48 h respectively, and a slow washout over 7 days (t1/2 > 230 h), with 0.35% CNS bioavailability. S1D12 inhibited the generation of aggregated tau, seed-competent tau and insoluble phosphorylated tau in transgenic mice. This was associated with a reduction in NfL and pTau217, and an increase in core tau in plasma. In the 4.5-month cohort, S1D12 did not remove already established tau aggregates below baseline. Additionally, S1D12 inhibited seeding tau species from different tauopathies to a similar degree, independent of structural diversity.

CONCLUSIONS: S1D12, a high-affinity antibody targeting the R4 repeat domain of tau offers potential for halting progression of tau pathology through inhibition of tau aggregation rather than removal of established aggregates. These findings support the notion that both early diagnosis and intervention are key for the treatment of AD and other tauopathies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01985-x.},
}

@article {pmid41881052,
year = {2026},
author = {Noguchi-Shinohara, M and Ono, K},
title = {Successful Amyloid Removal by Donanemab Treatment in a Female Patient With Alzheimer Disease: A Case Report.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214817},
doi = {10.1212/WNL.0000000000214817},
pmid = {41881052},
issn = {1526-632X},
}

@article {pmid41882255,
year = {2026},
author = {Yan, Y and Song, D and Li, G and Li, J and Tang, Y and Li, D and Mao, J and Li, H and Liu, X and Yu, D and Ma, F and Pang, Y and Jin, Y and Deng, Y and Qiu, Y and Quan, Z and Ni, J and Cheng, Y and Wang, Z and Dong, Z and Hong, Q},
title = {The dynamic impairment of synaptic transmission in the PCx-IL engram circuit contributes to early olfactory memory decline in Alzheimer's disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41882255},
issn = {1476-5578},
support = {82371446//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Olfactory dysfunction has emerged as a promising target for the early diagnosis and treatment of Alzheimer's disease (AD). However, the mechanisms underlying neural circuit disruption associated with olfactory dysfunction in AD remain poorly understood. We conducted single-cell RNA sequencing (RNA-seq) and ex vivo electrophysiological studies to determine the link between olfactory memory in AD and dynamic synaptic transmission disorders in PCx-IL engram cell circuits. Clinical functional magnetic resonance imaging (fMRI) data revealed that connectivity between the piriform cortex (PCx) and the infralimbic cortex (IL) was impaired during the early mild cognitive impairment (MCI) stage of AD. Optogenetic stimulation of IL-projecting PCx engram neurons successfully improved olfactory memory retrieval in 5xFAD mice. In addition, single-cell RNA sequencing was employed to investigate the mechanisms of damage in IL engram cells, which revealed increased glutamate expression and impaired synaptic function as key alterations. Guided by single-cell sequencing data, we analyzed glutamatergic synaptic transmission in the PCx-IL engram cell circuit in 5xFAD mice. These results indicated dynamic impairments in AMPA receptor-associated synaptic transmission within this circuit. Optical long-term potentiation (LTP) of synaptic transmission restored directional engram synaptic transmission and prevented olfactory memory decline. Therefore, dynamic impairment of synaptic transmission in the PCx-IL engram cell circuit underlies the early decline in olfactory memory in AD. Impairment of PCx-IL functional connectivity may represent a new target for the diagnosis and treatment of early-stage AD.},
}

@article {pmid41882372,
year = {2026},
author = {Hajjar, IM and Neal, R and Singh, N and Yang, Z and Obideen, M and Shah, AM and Dammer, EB},
title = {Adhesion molecules provide an endothelial protein signature in preclinical and clinical Alzheimer's disease and predict clinical progression.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01519-4},
pmid = {41882372},
issn = {2730-664X},
abstract = {BACKGROUND: Cardiometabolic and inflammatory pathways may play important roles in Alzheimer's disease (AD) pathogenesis contributing to neuronal dysfunction even in the absence of cognitive symptoms. Our objective is to characterize proteomic signatures of these pathways in AD.

METHODS: We perform CSF and plasma-targeted proteomics using Olink's highly sensitive proximity extension assay from 354 participants, of which 4.2% had preclinical AD, and 19.5% had prodromal AD. Using data-driven bioinformatic pipeline, we describe proteomic signatures based on various AD traits.

RESULTS: The 276 measured proteins cluster into five modules that are associated with AD biomarkers and disease traits. We identify an AD signature in the CSF characterized by elevated levels of Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecules 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2 (SCARB2), and Plasminogen Activator Urokinase (PLAU) that was detectable even in preclinical AD. This signature also predicts clinical disease progression. Independent validation (n = 75) suggests that CSF adhesion molecules showed significant positive correlation with CSF Aβ-42: (R[2] ranged: 0.05-0.44) and pTau (R[2] ranged: 0.15-0.70).

CONCLUSIONS: Our results identify a signature centered around CSF vascular adhesion proteins that associates with AD pathology and disease progression, with elevation detectable even in the preclinical stage, warranting further mechanistic investigation.},
}

@article {pmid41883102,
year = {2026},
author = {Cheng, B and Chen, Y and Cai, F and Wen, X},
title = {Therapeutic Potential of Salvia miltiorrhiza Active Components in Various Diseases Based on the PI3K/Akt Signaling Pathway.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {3},
pages = {e03444},
doi = {10.1002/cbdv.202503444},
pmid = {41883102},
issn = {1612-1880},
support = {No.GJJ2400803//Science and Technology Research Project of the Jiangxi Provincial Department of Education/ ; No.2024B0016//the Science and Technology Project of the Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; No.202410412151//the Student Innovation and Entrepreneurship Project of Jiangxi University of Chinese Medicine/ ; No.2025WBZR006//the Doctoral Research Startup Foundation Project of Jiangxi University of Chinese Medicine/ ; },
mesh = {Humans ; *Salvia miltiorrhiza/chemistry/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors ; *Signal Transduction/drug effects ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism ; Neoplasms/drug therapy/metabolism ; *Drugs, Chinese Herbal/chemistry/pharmacology ; *Phosphatidylinositol 3-Kinase/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Atherosclerosis/drug therapy/metabolism ; Diabetic Nephropathies/drug therapy/metabolism ; },
abstract = {Salvia miltiorrhiza Bunge, known as danshen in China, is a key medicinal herb in traditional Chinese medicine that has long been used for the treatment of cardiovascular and cerebrovascular disorders. Its principal bioactive constituents fall into two broad categories: water-soluble phenolic acids (primarily including danshensu, salvianic acid A, salvianolic acid B, and rosmarinic acid) and lipid-soluble diterpenoids (primarily including tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone). Accumulating evidence shows that these active components exert diverse pharmacological effects, including anti-tumor, anti-inflammatory, antioxidant, and anti-neurodegenerative activities, via modulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Consistently, these components hold promising therapeutic potential against various diseases, including cancer, atherosclerosis, Alzheimer's disease, and diabetic nephropathy. Nevertheless, there is still a lack of a comprehensive and systematic summary of the precise mechanisms by which the active ingredients of danshen exert their therapeutic actions against the aforementioned diseases via the PI3K/Akt signaling pathway. To address this gap, this review systematically summarizes the regulatory effects of danshen's active components on the PI3K/Akt signaling pathway, aiming to clarify their therapeutic potential in various pathological conditions and thereby provide novel insights for the basic research and clinical application of danshen.},
}

Humans
*Salvia miltiorrhiza/chemistry/metabolism
*Proto-Oncogene Proteins c-akt/metabolism/antagonists & inhibitors
*Signal Transduction/drug effects
Animals
*Phosphatidylinositol 3-Kinases/metabolism
Neoplasms/drug therapy/metabolism
*Drugs, Chinese Herbal/chemistry/pharmacology
*Phosphatidylinositol 3-Kinase/metabolism
Alzheimer Disease/drug therapy/metabolism
Atherosclerosis/drug therapy/metabolism
Diabetic Nephropathies/drug therapy/metabolism

@article {pmid41883280,
year = {2026},
author = {Bugnon, A and Temperli, P and Abbes, H and Doser, N},
title = {[Cerebral amyloid angiopathy-related inflammation and anti-amyloid immunotherapies].},
journal = {Revue medicale suisse},
volume = {22},
number = {955},
pages = {1-7},
doi = {10.53738/REVMED.2026.22.955.e47917},
pmid = {41883280},
issn = {1660-9379},
mesh = {Humans ; *Cerebral Amyloid Angiopathy/therapy/complications/diagnosis/immunology ; Alzheimer Disease/therapy ; *Immunotherapy/methods ; *Inflammation/therapy/etiology ; Prognosis ; },
abstract = {Cerebral amyloid angiopathy can be complicated by an inflammatory form known as CAA-ri (cerebral amyloid angiopathy-related inflammation), a rare but sometimes severe condition whose prognosis is improved by early diagnosis and treatment. CAA-ri shares physiopathological, clinical and radiological features with amyloid-related imaging abnormalities (ARIA), a complication observed during the development of novel anti-amyloid immunotherapies for Alzheimer's disease (AD). These ARIA are more frequent and severe in patients with CAA, requiring particular attention given the significant overlap between AD and this pathology. This article aims to raise awareness and improve recognition of these entities associated with amyloid deposition.},
}

Humans
*Cerebral Amyloid Angiopathy/therapy/complications/diagnosis/immunology
Alzheimer Disease/therapy
*Immunotherapy/methods
*Inflammation/therapy/etiology
Prognosis

@article {pmid41883437,
year = {2026},
author = {García Menéndez, S and Inserra, F and de Cavanagh, EM and Ferder, L and Manucha, W},
title = {Renin-angiotensin system blockade attenuates brain mitochondrial dysfunction, oxidative stress, and neuroinflammation associated with hypertension, metabolic disorders, and aging.},
journal = {World journal of experimental medicine},
volume = {16},
number = {1},
pages = {113259},
pmid = {41883437},
issn = {2220-315X},
abstract = {Although aging is an inherent part of life, it represents a process of progressive dysfunction rather than a fixed biological outcome. Consequently, highly prevalent conditions such as cardiorenal-metabolic syndrome-which encompasses obesity, hypertension (HTN), and metabolic disorders-can accelerate age-related changes. The renin-angiotensin system (RAS) plays a critical role in pathophysiology and affects multiple organs, including the brain. The central nervous system contains both RAS branches: The ACE/Ang II/AT1 and AT2 receptor axis, as well as the ACE2/Ang-(1-7)/Mas receptor axis. Neuroinflammation is a chronic process characterized by glial cell activation triggered by increased production of reactive oxygen and nitrogen species, resulting in oxidative stress. Mitochondria are the primary cellular sites where these processes occur. Under conditions such as metabolic disorders, obesity, HTN, and aging, these reactions are markedly accelerated. Associated mechanisms include insulin resistance, elevated levels of advanced glycation end-products, and disruption of the blood-brain barrier. The consequences of these alterations may include brain dysfunction, cognitive decline, Parkinson's disease, and neurodegenerative conditions such as Alzheimer's disease. This review focuses on the primary effects of therapeutic interventions on mitochondrial function, with particular attention to the modulation of oxidative stress, chronic neuroinflammation, and glial dysregulation. We highlight the strategic use of angiotensin receptor blockers and ACE2 activators as promising tools that may redefine the prevention and treatment of vascular dementia and other neurodegenerative diseases of inflammatory origin.},
}

@article {pmid41884282,
year = {2026},
author = {Chu, H and Sun, Y and Huang, C and Wang, L and Guo, Q and Jiang, L},
title = {Polydopamine Modified with Brain Targeting Peptide Rabies Virus Glycoprotein for Treatment of Alzheimer's Disease by Inhibiting Oxidative Stress and Inflammatory Response.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {564013},
pmid = {41884282},
issn = {1178-2013},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology ; Oxidative Stress/drug effects ; *Indoles/chemistry/pharmacology/administration & dosage ; Mice ; *Polymers/chemistry/pharmacology/administration & dosage ; *Glycoproteins/chemistry/pharmacology/administration & dosage ; Nanoparticles/chemistry ; Brain/drug effects/metabolism ; *Viral Proteins/chemistry/pharmacology/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; Humans ; Inflammation/drug therapy ; Male ; Ferroptosis/drug effects ; Peptide Fragments ; },
abstract = {PURPOSE: Polydopamine (PDA) has been recognized as an antioxidant and anti-inflammatory agent. However, the difficulty to cross blood-brain barrier (BBB) limits PDA's neuroprotective effects in the brain. Here, we aimed to construct PDA-rabies virus glycoprotein (RVG) by modifying the RVG29 polypeptide on PDA nanoparticles (NPs) and investigate whether PDA-RVG improved the cognitive function and pathology of Alzheimer's Disease (AD) by inhibiting oxidative stress and inflammatory response.

METHODS: We prepared and characterized PDA NPs and tested whether PDA improved AD pathology in APP/PS1 mice. To facilitate PDA's penetration across BBB, we modified RVG29 on PDA and examined its brain-specific targeting ability and biocompatibility. We further tested the effects of PDA-RVG on oxidative stress, inflammatory response and ferroptosis in both in vitro and in vivo AD models.

RESULTS: PDA demonstrated robust reactive oxygen species (ROS)-scavenging activity and effectively reduced Aβ deposition and the expression of APP and PS1 in APP/PS1 mice. PDA-RVG successfully crossed BBB in an in vitro BBB model. Meanwhile, compared with PDA, PDA-RVG intravenous injection exhibited good brain-specific targeting ability. Moreover, the hematological analysis revealed no significant differences between the PDA-RVG and control groups. In the in vitro AD experiment, PDA-RVG reduced ROS, inducible nitric oxide synthase, and pro-inflammatory cytokines levels in BV2 cells. Besides, PDA-RVG decreased ROS and apoptosis, while increased glutathione peroxidase4 (GPX4) and the viability of PC12 cells. More importantly, intravenous delivery of PDA-RVG improved cognitive function assessed by Morris water maze, and upregulated the ferroptosis-protective proteins Ferritin Heavy Chain 1 and GPX4 expression, while PDA alone did not lead to cognitive improvement.

CONCLUSION: PDA reduces AD pathology, which is possibly attributed to its ability to scavenge ROS, ameliorate the inflammatory microenvironment and inhibit ferroptosis. Intravenous delivery of PDA-RVG has good brain-specific targeting ability and biocompatibility, and improves cognitive function in AD mice. This study provides a safe, effective, and promising therapeutic strategy for AD via oxidative stress-associated target.},
}

Animals
*Alzheimer Disease/drug therapy/pathology
Oxidative Stress/drug effects
*Indoles/chemistry/pharmacology/administration & dosage
Mice
*Polymers/chemistry/pharmacology/administration & dosage
*Glycoproteins/chemistry/pharmacology/administration & dosage
Nanoparticles/chemistry
Brain/drug effects/metabolism
*Viral Proteins/chemistry/pharmacology/administration & dosage
Blood-Brain Barrier/metabolism/drug effects
Disease Models, Animal
Neuroprotective Agents/pharmacology/administration & dosage/chemistry
Reactive Oxygen Species/metabolism
Mice, Transgenic
Humans
Inflammation/drug therapy
Male
Ferroptosis/drug effects
Peptide Fragments

@article {pmid41884668,
year = {2026},
author = {Xia, L and Liu, T and Li, Z and Ao, X and Chen, Q and Zhou, X and Jiang, Q and Huang, N and Luo, Y},
title = {Icaritin ameliorates mitochondrial dysfunction and autophagy impairment in cellular models of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1741339},
pmid = {41884668},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory decline, with neuropathological hallmarks including amyloid plaques and neurofibrillary tangles. Current treatments only alleviate symptoms and cannot halt disease progression. Icaritin (ICT), a natural compound, has shown neuroprotective potential. Transactive response DNA-binding protein 43 (TDP-43) is widely recognized as a key neuropathological hallmark of AD and related dementias. This study investigated the protective effects of ICT against TDP-43-induced damage in N2a/APP695swe (APP) cells and explored the underlying mechanisms.

METHODS: N2a/APP695swe/TARDBP cells overexpressing APP and TDP-43 were constructed via lentiviral transfection, and the optimal ICT dosage was determined using the CCK-8 assay. The effects of ICT on TDP-43 cell phenotypes were then assessed using CCK-8, ELISA, and Western blot. Finally, transmission electron microscopy, flow cytometry, assay kits, and Western blot were used to investigate the protective mechanisms of ICT.

RESULTS: ICT treatment significantly increased cell viability, reduced Aβ42 levels, and alleviated phospho-Tau and phospho-TDP-43 accumulation. Mechanistically, ICT improved mitochondrial morphology, decreased ROS levels, enhanced ATP production, and modulated the AMPK/mTOR and PINK1/Parkin autophagy signaling pathways to mitigate TDP-43-mediated cellular stress.

CONCLUSION: ICT protects cells from TDP-43-induced mitochondrial dysfunction and autophagy impairment, providing mechanistic insight into its potential as a therapeutic agent for AD.},
}

@article {pmid41885175,
year = {2026},
author = {Young, CB and Sheng, J and Winer, JR and Cody, K and Sai, I and Carlson, ML and Younes, K and Insel, PS and Schultz, AP and Mormino, EC},
title = {Longitudinal trajectories of divergent cortical tau patterns in preclinical Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag113},
pmid = {41885175},
issn = {1460-2156},
abstract = {Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer's disease) have "divergent" cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical regions relative to medial temporal lobe and/or cortical asymmetry on tau PET in addition to or instead of traditional medial temporal lobe tau burden. Although these A+TCortical+ individuals have subtle cognitive deficits at baseline, the longitudinal imaging and clinical outcomes are unknown. We aimed to characterize longitudinal trajectories of A+TCortical+ individuals compared to other biomarker-defined clinically unimpaired groups given that identifying those at highest risk for decline is critical for informing prevention trials and understanding early disease mechanisms. In this longitudinal study, we examined tau PET, MRI, cognitive, and functional data from 395 clinically unimpaired participants, ages 65 to 85 years, enrolled in the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study. Participants had 2-5 flortaucipir scans over a mean (standard deviation) follow-up period of 4.7 (1.6) years. Change in regional and voxelwise tau patterns, atrophy, cognition, and functioning were examined. Longitudinal trajectories from A+TCortical+ (n=34) were compared to preclinical Alzheimer's disease with elevated tau PET signal in medial temporal lobe only (A+TMTL+, n=102), preclinical Alzheimer's disease without significant tau (A+TMTL-, n=210), and those without amyloid or tau (A-TMTL-, n=49). Cortical tau accumulation was fastest in A+TCortical+ (0.018-0.034 standardized uptake value ratios per year), whereas medial temporal lobe tau accumulation was comparable across A+TCortical+, A+TMTL+, and A+TMTL- groups (0.010-0.013 standardized uptake value ratios per year). Tau continued to accumulate in affected regions and contralateral homotopic regions in A+TCortical+ participants with asymmetrical tau at baseline such that asymmetrical patterns were maintained over time. Younger A+TCortical+ participants had an especially fast cortical accumulation rate. The A+TCortical+ group showed significantly greater neurodegeneration and faster clinical decline (Clinical Dementia Rating Scale Sum of Boxes = 0.610 points per year; Mini-Mental State Examination = -0.780 points per year) than all other biomarker-defined subgroups (Clinical Dementia Rating Scale Sum of Boxes = 0.048-0.182 points per year; Mini-Mental State Examination = -0.189-0.006 points per year). In summary, individuals with divergent cortical tau patterns continue to accumulate cortical tau at a faster rate, show greater neurodegeneration, and have faster cognitive and functional decline than other preclinical Alzheimer's disease subgroups. Clinical trials and research examining tau progression and clinical decline in preclinical Alzheimer's disease without subtyping may be disproportionately influenced by this small, high-risk subgroup.},
}

@article {pmid41885326,
year = {2026},
author = {Dangpiaei, S and Kamal, KM and Shoair, OA and Al-Mamun, MA},
title = {Incidence of amyloid-related imaging abnormalities and health resource utilization in patients with Alzheimer disease receiving monoclonal antibody treatments: A real-world evidence study.},
journal = {Journal of managed care & specialty pharmacy},
volume = {32},
number = {4},
pages = {470-484},
doi = {10.18553/jmcp.2026.32.4.470},
pmid = {41885326},
issn = {2376-1032},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Female ; Aged ; Male ; Retrospective Studies ; Aged, 80 and over ; Incidence ; *Antibodies, Monoclonal/adverse effects/therapeutic use ; Middle Aged ; *Health Resources/statistics & numerical data ; Patient Acceptance of Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: All recently approved monoclonal antibodies (eg, aducanumab, lecanemab, and donanemab) for Alzheimer disease (AD) were shown to increase the risks of amyloid-related imaging abnormalities (ARIA) in randomized clinical trials, which can include brain swelling or hemorrhage. Real-world evidence (RWE) studies are critically warranted to evaluate the associated risks of ARIA and health care resource utilization (HRU) with monoclonal treatments compared with existing nonmonoclonal (eg, donepezil, memantine and rivastigmine) treatments.

OBJECTIVE: To evaluate the risk of ARIA in patients receiving monoclonal vs nonmonoclonal treatments. The secondary aim was to investigate the HRUs including emergency department (ED) and inpatient visits between the 2 groups.

METHODS: We conducted a retrospective study using a large electronic health record dataset. Individuals (aged ≥18 years) diagnosed with AD and receiving monoclonal treatment were matched with a nonmonoclonal treatment group using propensity score matching. An Andersen-Gill survival model was used to estimate the cumulative hazard of ARIA after adjusting for baseline comorbidities. Negative binomial regression was applied to assess the HRUs between the 2 groups.

RESULTS: The monoclonal group included 240 patients. Most patients in both groups were aged 70-80 years (47.08% vs 47.29%), female (55.42% vs 56.25%), and White (85.42% vs 85.83%) in the monoclonal and the nonmonoclonal groups, respectively. The monoclonal group had significantly higher cumulative hazard of ARIA (hazard ratio = 4.65, 95% CI = 3.77-5.73; P < 0.001) compared with the nonmonoclonal group. Concurrent antithrombotic use (1.87, 1.48-2.37; P < 0.001), a history of stroke (1.59, 1.21-2.10; P < 0.001), and hyperlipidemia (1.41, 1.09-1.84; P = 0.008) were also associated with increased hazard of ARIA. Among those patients who had at least 180 days of follow-up, the monoclonal group had significantly fewer inpatient visits (β = -2.71, -3.84 to -1.58; P < 0.001) compared with the nonmonoclonal group.

CONCLUSIONS: Monoclonal treatment was associated with higher cumulative hazard of ARIA but fewer inpatient visits. This study indicated the potential of RWE, despite its distinct observational design and differences from randomized clinical trials, to serve as a credible proof-of-concept in postapproval assessment and to inform personalized treatment guidelines based on patients' risk factors.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging
Female
Aged
Male
Retrospective Studies
Aged, 80 and over
Incidence
*Antibodies, Monoclonal/adverse effects/therapeutic use
Middle Aged
*Health Resources/statistics & numerical data
Patient Acceptance of Health Care/statistics & numerical data

@article {pmid41885876,
year = {2026},
author = {Wang, J and Zhang, B and Liu, L and Li, X and Xie, Z and Yang, X},
title = {Vanadyl Complexes (VOp-Dmada) Promote Healthy Aging by Regulating Electron Transport Mediated by Mitochondrial Complex II.},
journal = {ChemMedChem},
volume = {21},
number = {6},
pages = {e202600003},
doi = {10.1002/cmdc.202600003},
pmid = {41885876},
issn = {1860-7187},
support = {22177007//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Mice ; *Electron Transport Complex II/metabolism/antagonists & inhibitors ; Electron Transport/drug effects ; *Mitochondria/metabolism/drug effects ; *Healthy Aging/drug effects ; *Coordination Complexes/pharmacology/chemistry/chemical synthesis ; Caenorhabditis elegans/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Structure ; Structure-Activity Relationship ; Dose-Response Relationship, Drug ; *Vanadium Compounds/pharmacology/chemistry ; },
abstract = {Vanadium compounds are promising metallodrug candidates, with well-documented antidiabetic, antitumor, and anti-Alzheimer's activities. In search for the long-term beneficial or adverse effects of antidiabetic vanadyl complexes, we serendipitously discovered that the vanadyl complexes VOp-dmada exerted pro-healthy aging effects across a diverse panel of model organisms, i.e., yeast, C. elegans, and SAMP8 mice. Furthermore, VOp-dmada attenuated replicative senescence in mouse embryonic fibroblasts and alleviated thymic epithelial cell aging while preserving thymic architecture and function in a mouse model of dexamethasone-induced acute thymic atrophy. Mechanistic investigations revealed that VOp-dmada improved the structural integrity and functional capacity of mitochondrial complex II. This effect was mediated by activation of the c-Myc/S-phase kinase-associated protein 2 (SKP2)/sirtuin 3 (SIRT3) signaling axis, which in turn upregulated succinate dehydrogenase subunit A (SDHA) expression. Thus, vanadyl complexes suppressed reactive oxygen species (ROS) generation at the source, disrupted the deleterious ROS-thioredoxin-interacting protein (TXNIP) vicious cycle, and ultimately decelerated the aging process. Our findings highlight the potential application of antidiabetic vanadium complexes in the treatment of other aging-related disorders and corroborate the chronic safety profile. Moreover, these results support the targeting of mitochondrial complex II function and integrity as a novel strategy for the discovery of pro-healthy aging agents.},
}

Animals
Mice
*Electron Transport Complex II/metabolism/antagonists & inhibitors
Electron Transport/drug effects
*Mitochondria/metabolism/drug effects
*Healthy Aging/drug effects
*Coordination Complexes/pharmacology/chemistry/chemical synthesis
Caenorhabditis elegans/drug effects
Reactive Oxygen Species/metabolism
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
*Vanadium Compounds/pharmacology/chemistry

@article {pmid41886471,
year = {2026},
author = {Luo, N and Pandit, H and Kalra, S and Tran, E and Mandelblatt, J and Vicini, S and Rebeck, GW},
title = {APOE4 and doxorubicin impair inhibitory interneuron function and homeostatic regulation in the entorhinal cortex.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0343276},
doi = {10.1371/journal.pone.0343276},
pmid = {41886471},
issn = {1932-6203},
mesh = {Animals ; *Doxorubicin/pharmacology/adverse effects ; *Apolipoprotein E4/genetics/metabolism ; *Entorhinal Cortex/drug effects/metabolism/physiology ; *Interneurons/drug effects/metabolism/physiology ; Mice ; *Homeostasis/drug effects ; Pyramidal Cells/drug effects/metabolism/physiology ; Humans ; Parvalbumins/metabolism ; Male ; Female ; Genotype ; Mice, Transgenic ; },
abstract = {APOE4 is a risk factor for several disease states associated with cognitive impairment, including Alzheimer's disease and cancer-chemotherapy induced cognitive impairment. Using mouse knock-in models of human APOE alleles, we examined the effects of APOE genotype and chemotherapy on the ex vivo electrophysiological characteristics of excitatory and inhibitory neurons in the entorhinal cortex (EC). We found that APOE4 is associated with a significantly higher excitatory/inhibitory ratio (0.33 ± 0.04) in the layer 2/3 pyramidal cells of the entorhinal cortex compared to APOE3 (0.19 ± 0.04). We crossed APOE mice to mice with parvalbumin (PV) interneurons tagged with tdTomato, allowing us to measure effects specifically on this inhibitory cell type. For EC pyramidal neurons, the chemotherapeutic agent doxorubicin caused increases in the amplitudes of both spontaneous excitatory and inhibitory post-synaptic currents, with significant responses (***p < 0.001; **p < 0.01 respectively) in APOE3 brains. For EC PV neurons, APOE4 genotype was associated with significantly lower firing rates at injections of high currents (**p < 0.01), but rates were unaffected by doxorubicin. Doxorubicin doubled the percentage of PV cells that showed inactivation block in APOE3 brains (25% to 52%) but had no effect on APOE4 brains (50% to 54%). This ex vivo study suggests that APOE4 impairs homeostatic synaptic transmission in pyramidal cells under control conditions and causes a lack of responsiveness to a stressor (doxorubicin treatment) in PV cells.},
}

Animals
*Doxorubicin/pharmacology/adverse effects
*Apolipoprotein E4/genetics/metabolism
*Entorhinal Cortex/drug effects/metabolism/physiology
*Interneurons/drug effects/metabolism/physiology
Mice
*Homeostasis/drug effects
Pyramidal Cells/drug effects/metabolism/physiology
Humans
Parvalbumins/metabolism
Male
Female
Genotype
Mice, Transgenic

@article {pmid41699585,
year = {2026},
author = {Zhang, R and Chen, D and Qin, Y and Han, H and Yu, H},
title = {Longitudinal multi-modal data prediction model for mild cognitive impairment by deep survival analysis.},
journal = {BMC medical informatics and decision making},
volume = {26},
number = {1},
pages = {},
pmid = {41699585},
issn = {1472-6947},
abstract = {BACKGROUND: Timely prediction of cognitive decline in patients with Mild Cognitive Impairment (MCI) is crucial for guiding optimal therapeutic interventions. In this study, we aimed to develop a deep survival analysis model that leverages longitudinal, multi-modal data to estimate the probability of dementia conversion, thereby facilitating personalized treatment planning in clinical practice.

METHODS: We employed a deep neural network model specifically designed for survival analysis to predict the progression from MCI to Alzheimer’s Disease (AD). The model integrated longitudinal biomarkers, including neuropsychological assessments and neuroimaging measures, along with baseline demographic characteristics and genetic risk factors, using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

RESULTS: This study enrolled 922 baseline MCI patients for analysis. The predictive performance was evaluated using a test set at time intervals [Formula: see text] = 1, 2, 3, 4 years from the landmark time s = 1. The prognostic model exhibited outstanding predictive capability, attaining cdAUC values of 0.9089 ± 0.01 alongside BS of 0.1651 ± 0.01 with [Formula: see text] = 1 year on the test set, when all variable sets were incorporated into the time-dependent Cox survival neural network (tdCoxSNN) model. Through feature significance evaluation, the Functional Activities Questionnaire (FAQ) emerged as the most influential predictive element.

CONCLUSIONS: By systematically integrating diverse longitudinal biomarkers, we developed a dynamic prediction model for MCI using deep survival analysis. This approach enables accurate individual risk stratification, facilitates the early identification of high-risk individuals, and supports informed, personalized clinical decision-making.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12911-026-03387-3.},
}

@article {pmid41876052,
year = {2026},
author = {Harutyunyan, H and Minasyan, R and Kalueff, AV and Yenkoyan, KB},
title = {Neurobiological links between Alzheimer's disease and reward system dysfunction.},
journal = {Neuroscience},
volume = {603},
number = {},
pages = {57-68},
doi = {10.1016/j.neuroscience.2026.03.028},
pmid = {41876052},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a highly prevalent progressive neurodegenerative disorder with unclear etiology, complex symptoms, and limited treatment options. Early pathological processes in AD emerge long before the onset of overt cognitive and motor symptoms and involve the accumulation of amyloid-β oligomers and neurofibrillary tangles, accompanied by neuroinflammation and neuronal loss. Importantly, the brain reward system comprises cortical and subcortical structures that share neurochemical pathways and reciprocal connectivity with regions affected during AD progression. Consistent with this overlap, reward-related behavioral deficits, including apathy, anhedonia, and motivational impairments, are frequently observed in both patients with AD and experimental models of the disease. Here, we discuss the neuroanatomical, neurochemical, and molecular overlap between AD pathology and reward-related neural circuits and propose that dysfunction of the reward system may represent an important pathogenetic endophenotype of AD. A better understanding of these multilevel interactions may help refine the conceptual framework of AD and support the development of novel therapeutic strategies targeting reward-related circuits and their underlying molecular mechanisms.},
}

@article {pmid41877272,
year = {2026},
author = {Scenna, MS and Maceroni, E and Cimini, A and Castelli, V and d'Angelo, M},
title = {Hypertension and brain damage: evidence from rodent models.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41877272},
issn = {1738-6055},
abstract = {Hypertension is a prevalent condition that significantly raises the incidence of cerebrovascular and cognitive disorders. This review focuses on the factors most closely linked to stroke, cognitive impairment, and Alzheimer's disease. Research into pathophysiology and treatment of hypertensive brain damage has greatly benefited from rodent models, which have been crucial in uncovering the underlying mechanisms and developing effective therapeutic strategies. Rodent models, particularly spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHR-SP), have been essential in elucidating the pathophysiological mechanisms connecting hypertension to brain damage. These models exhibit structural and functional cerebrovascular alterations, including blood-brain barrier disruption, microvascular rarefaction, and neuroinflammation. Interventions targeting the renin-angiotensin system have shown promise in mitigating these adverse effects. This review synthesizes current findings from rodent studies, underscoring the pivotal impact of hypertension in brain pathology and the potential therapeutic benefits of antihypertensive treatments.},
}

@article {pmid41877626,
year = {2026},
author = {Zhou, X and Wang, R and Yan, J and Wu, X and Yuan, D and Wang, Q and Li, H and Zhao, W},
title = {Atractylenolide I mitigates Alzheimer's disease pathology in ApoE [-/-] mice via ARG1/nNOS axis and lipid homeostasis regulation.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2026055},
pmid = {41877626},
issn = {1745-7270},
abstract = {Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephalaKoidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE [-/-]) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by upregulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, and creatinine) to rebalance neurovascular homeostasis. Notably, western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.},
}

@article {pmid41877664,
year = {2026},
author = {Pennington, C and Apurva, P and Chen, A and Duncan, A and Mackay, G and Masters, H and Paramore, K and Russ, T and Skinner, H and Zeidler, M},
title = {Disease modifying treatments for Alzheimer's disease: Clinician perspectives.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261429859},
doi = {10.1177/13872877261429859},
pmid = {41877664},
issn = {1875-8908},
abstract = {In recent years there have been exciting developments in the diagnosis and treatment of mild cognitive impairment and dementia due to Alzheimer's disease. Robust biomarkers and potentially disease modifying therapies are now available, with multiple other agents in clinical trials alongside on-going validation studies of blood-based biomarkers. Recent and probable future developments in the diagnosis and care of people with Alzheimer's disease pathology warrants serious re-evaluation of the structure and function of cognitive clinical services. Here we report recommendations from the November 2024 Brain Health Scotland roundtable discussion of opportunities and challenges for modern memory services.},
}

@article {pmid41878314,
year = {2026},
author = {Tang, S and Liao, Y and Yang, M and Yue, R},
title = {Brain insulin resistance: a key pathological hub linking metabolic and neuropsychiatric comorbidities.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1716291},
pmid = {41878314},
issn = {1663-4365},
abstract = {The high rate of comorbidity between metabolic diseases and neuropsychiatric disorders suggests a shared underlying pathogenic mechanism. However, the biological basis of this relationship remains unclear. This study aims to clarify the role of brain insulin resistance (BIR) in linking metabolic dysfunction to neuropsychiatric symptoms based on existing evidence. The analysis shows that BIR disrupts limbic system function through two primary molecular pathways: (1) impairment of the PI3K/Akt/mTOR pathway, which decreases the expression of synaptic plasticity-related proteins and causes deficits in long-term potentiation (LTP); (2) activation of the TLR4/MyD88 inflammatory axis, promoting pro-inflammatory cytokine release from glial cells. These changes result in characteristic neuropsychiatric phenotypes, including amygdala hyperactivity (emotional disorders), hippocampal atrophy (memory impairment), and decreased prefrontal cortex (PFC) function (executive dysfunction). This review highlights that interventions targeting BIR might simultaneously improve metabolic outcomes and neuropsychiatric symptoms, providing a theoretical foundation for trans-diagnostic treatment models. The findings support the view of BIR as a modifiable interface for metabolic- neuropsychiatric comorbidities and advocate for the development of a multidisciplinary collaborative framework to facilitate mechanism-based precision therapy.},
}

@article {pmid41879387,
year = {2026},
author = {Cheng, J and Zhang, C and Yang, L and Li, G and Jiang, X and Chen, P and Duan, X},
title = {An integrated strategy including chemical profiling, network pharmacology and experimental evaluation was used to investigate the effects of Rubia yunnanensis water decoction on vascular dementia.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {5},
pages = {1262-1283},
doi = {10.36721/PJPS.2026.39.5.REG.14029.1},
pmid = {41879387},
issn = {1011-601X},
mesh = {Animals ; *Network Pharmacology/methods ; *Dementia, Vascular/drug therapy/metabolism/pathology/psychology ; *Drugs, Chinese Herbal/pharmacology/chemistry ; Rats ; *Neuroprotective Agents/pharmacology ; Male ; Rats, Sprague-Dawley ; Disease Models, Animal ; Signal Transduction/drug effects ; Apoptosis/drug effects ; },
abstract = {BACKGROUND: Vascular dementia (VaD) is the second most prevalent cause of dementia following Alzheimer's disease. Rubia yunnanensis, a medicinal plant recorded in the Chinese Materia Medica, has historically been utilized for managing cerebral ischaemia-related disorders. While recent attention has focused on its neuroprotective potential, the specific mechanisms underlying the effects of Rubia yunnanensis water decoction (RY-W) on VaD remain unelucidated.

OBJECTIVES: This study aimed to identify the active chemical components and elucidate the molecular mechanisms of RY-W in the treatment of VaD by integrating network pharmacology with experimental validation.

METHODS: The chemical constituents of RY-W and their potential therapeutic targets were analyzed using UPLC-MS/MS and network pharmacology techniques. To validate these findings, the cerebral protective effects of RY-W were assessed in a rat model of VaD. Cognitive function was evaluated using the Morris Water Maze (MWM) test. Pathological changes and molecular markers were analyzed via Hematoxylin and Eosin (HE) staining, Nissl staining, TUNEL fluorescence staining, Immunohistochemistry (IHC), and Western blotting.

RESULTS: Network pharmacology analysis identified IL-6, IL-1β, ALB, TNF, and AKT1 as potential core targets for RY-W. Experimental results demonstrated that RY-W significantly alleviated cognitive deficits in VaD rats. Furthermore, RY-W exhibited anti-inflammatory properties and reduced neuronal apoptosis. These neuroprotective effects appear to be mediated through the regulation of ALB and the PI3K-Akt signaling pathway.

CONCLUSION: RY-W effectively ameliorates VaD pathology by exerting anti-inflammatory and anti-apoptotic effects. These findings highlight the involvement of ALB and the PI3K-Akt signaling pathway in the therapeutic action of RY-W, supporting its potential as a treatment for vascular dementia.},
}

Animals
*Network Pharmacology/methods
*Dementia, Vascular/drug therapy/metabolism/pathology/psychology
*Drugs, Chinese Herbal/pharmacology/chemistry
Rats
*Neuroprotective Agents/pharmacology
Male
Rats, Sprague-Dawley
Disease Models, Animal
Signal Transduction/drug effects
Apoptosis/drug effects

@article {pmid41879434,
year = {2026},
author = {Hu, S and Chen, Z and Fu, Y},
title = {EEG Oscillations and the Modulation of tES and TMS in Patients with Mild Cognitive Impairment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050430368260120052142},
pmid = {41879434},
issn = {1875-5828},
abstract = {Mild cognitive impairment (MCI) is characterized by objective cognitive decline that does not severely impact daily independence. This clinical stage may stem from various underlying causes, including Alzheimer's disease pathology. MCI provides a valuable opportunity to study interventions that could slow cognitive decline. Individuals with MCI show alterations in neural oscillations linked to cognitive impairment. Non-invasive brain stimulation (NIBS) techniques, including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), along with their major forms, transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), can effectively modulate neural oscillations and improve cognition in MCI patients. Due to the potential of NIBS in the treatment of MCI, this review focuses on EEG abnormalities of neural oscillations in MCI patients and examines how repetitive TMS (rTMS), tDCS, and tACS improve cognitive function by targeting specific EEG frequency bands. A literature review was conducted for this study using the PubMed database, including studies published up to May 2025. Studies demonstrated that MCI patients have significant changes in EEG activity, with increases in the low-frequency band (δ-θ, 0.5-8 Hz) and decreases in the high-frequency band (β-γ, 12-100 Hz), and there are few reports on changes in mid-frequency α (8-12 Hz) EEG activity. Notably, tDCS improves cognition in MCI patients by decreasing low-frequency and increasing highfrequency EEG activity, whereas rTMS and tACS achieve similar effects mainly by increasing highfrequency EEG activity. Overall, this review provides an understanding of the role of NIBS in modulating neural oscillations and improving cognition in MCI, which may guide future therapeutic strategies. Future studies could explore the specific molecular pathways of neural oscillatory dysfunction in MCI and investigate the correlation between neural oscillations and other biomarkers, such as amyloid plaques and tau tangles, for a more comprehensive understanding of the disease.},
}

@article {pmid41879436,
year = {2026},
author = {Hu, G and Zhang, M},
title = {Efficacy and Safety of Donanemab in the Treatment of Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050425914260119063736},
pmid = {41879436},
issn = {1875-5828},
abstract = {INTRODUCTION: Donanemab is a monoclonal antibody targeting amyloid-β plaques. This study aims to quantify donanemab's consistent cognitive benefits, biomarker efficacy, and safety risks by pooling data from all available RCTs.

MATERIALS AND METHODS: Systematic searches were conducted in PubMed, the Cochrane Library, Web of Science, and Embase. Phase II/III randomized controlled trials comparing donanemab with placebo in amyloid-positive early Alzheimer's disease were included. After screening 133 records, two trials met the inclusion criteria.

RESULTS: Donanemab significantly reduced cognitive decline (iADRS +2.93; 95% CI: 1.52- 4.33; P < 0.0001) and functional progression (CDR-SB -0.66; 95% CI: -0.90 to -0.42; P < 0.00001), with amplified benefits in low/medium tau burden patients (iADRS +3.80; 95% CI: 2.10- 5.50). Amyloid clearance was dramatically higher with donanemab (risk ratio (RR) = 234.46; 95% CI: 68.17-806.38; P < 0.00001), with 76.4% achieving amyloid-negative status. There were significantly elevated risks of ARIA-E (RR = 12.90; 95% CI: 8.15-20.43; P < 0.00001), ARIA-H (RR = 2.86; 95% CI: 1.61-5.06; P = 0.0003), and treatment discontinuation (RR = 3.26; 95% CI: 2.38- 4.47; P < 0.00001), whereas all-cause mortality was not significantly different (RR = 1.44; 95% CI: 0.69-3.00).

DISCUSSION: Donanemab showed statistically significant cognitive benefits, but its clinical meaningfulness warrants careful interpretation. The iADRS improvement of 2.93 points and the CDRSB reduction in all patients of 0.66 points did not approach their minimal clinically important difference (MCID).

CONCLUSION: Donanemab provides statistically significant but modest benefits in early AD, particularly in low-tau subgroups. However, the magnitude of cognitive and functional improvement did not approach the threshold for a MCID in the overall population, which requires stringent safety monitoring for ARIA. Clinical implementation should prioritize PET stratification and APOEguided surveillance.},
}

@article {pmid41871009,
year = {2026},
author = {Hallam, RD and Foran, G and Fletcher, NK and MacPherson, REK and Necakov, A},
title = {BDNF alters β-cleavage of APP and subcellular distribution of BACE1.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00642.2025},
pmid = {41871009},
issn = {1522-1563},
support = {PGS-D//Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; PGS-D//NSERC | RES'EAU-WaterNET/ ; RGPIN-2017-03904//NSERC | RES'EAU-WaterNET/ ; RGPIN-2018-06781//NSERC | RES'EAU-WaterNET/ ; },
abstract = {The accumulation and deposition of amyloid-beta (Aß) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing of APP is tightly regulated by the opposing activities of BACE1 and ADAM10, with the latter producing a truncated, non-amyloidogenic fragment. Maintaining this balance is critical for normal physiological function, as complete inhibition of BACE1 has proven detrimental owing to the important physiological roles of its many substrates. Brain-derived neurotrophic factor (BDNF), an important mediator of neuronal function and survival, has recently been shown to reduce BACE1 activity in neural tissue, but the mechanism for this remains unknown. Previous research suggests that BACE1 cleavage of APP is favoured at acidic intracellular compartments, whereas non-amyloidogenic processing preferentially occurs at the plasma membrane. Hence, we hypothesized that BDNF alters the subcellular distribution of BACE1, reducing ß-cleavage of APP. Here, we show that acute BDNF treatment of differentiated neural cells (SH-SY5Y) reduced levels of sAPPß, a product of BACE1 cleavage of APP. Using confocal microscopy and quantitative image analysis, we found that this reduction in sAPPß levels is coincident with increased BACE1 localization to the plasma membrane, and a concomitant reduction of BACE1 localization to early endosomes. This effect appears to be independent of clathrin-mediated endocytosis (CME), as inhibition of CME by PitStop2 treatment increased a-cleavage of APP but did not reduce ß-cleavage independent of BDNF treatment. Hence, BDNF may reduce production of Aß by altering BACE1 distribution and decreasing upstream ß-cleavage.},
}

@article {pmid41872339,
year = {2026},
author = {Vrillon, A and Götze, K and Dumurgier, J and Cognat, E and Hourrègue, C and Munoz-Musat, E and Decaix, T and Hugon, J and Estrada, J and Sebbagh, M and Bouaziz-Amar, É and Lilamand, M and Paquet, C},
title = {Eligibility for lecanemab treatment in a French memory clinic setting.},
journal = {Journal of neurology},
volume = {273},
number = {4},
pages = {},
pmid = {41872339},
issn = {1432-1459},
support = {1310194//Foundation Alzheimer Young Researcher Program/ ; },
mesh = {Humans ; Female ; Male ; Aged ; France ; Retrospective Studies ; *Alzheimer Disease/drug therapy/cerebrospinal fluid/diagnosis ; Aged, 80 and over ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Eligibility Determination ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Patient Selection ; },
abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies, including lecanemab and donanemab, are now available for the treatment of Alzheimer's disease (AD). Defining real-world patient eligibility and identifying barriers to access are critical for their effective implementation in routine clinical practice.

METHODS: Retrospective observational multicenter study of patients who underwent CSF AD biomarker testing at Lariboisière Hospital (Paris, France) from 2023 to 2024, assessing lecanemab eligibility using CLARITY AD trial criteria and the French Memory Clinic Federation appropriate use recommendations (AURs) following EMA authorization.

RESULTS: From a source population of 3075 patients, 676 underwent CSF testing, and 356 had biomarker-confirmed AD; 315 patients with MRI, APOE status, and MMSE data available (mean age 73.2 ± 8.1 years; 47.8% female; median MMSE 22 [IQR 19-26]) were screened. Using CLARITY AD trial criteria, 90 patients (28.6%) were eligible; low MMSE scores and MRI findings were the most frequent exclusion criteria. French AURs reduced eligibility to 75 patients (23.8%), excluding patients with a CSF A + T - profile and APOE ε4 homozygotes. Eligibility did not differ by age group. Eligibility rates from the entire source population equated to only 2.9% of patients using the CLARITY AD criteria and 2.4% using the French AURs. At follow-up, 34.5% of initially eligible patients no longer met the MMSE eligibility criteria.

DISCUSSION: In specialized settings, lecanemab eligibility remained limited, highlighting the need for early AD diagnosis and efficient screening pathways.},
}

Humans
Female
Male
Aged
France
Retrospective Studies
*Alzheimer Disease/drug therapy/cerebrospinal fluid/diagnosis
Aged, 80 and over
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use
*Eligibility Determination
Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
*Patient Selection

@article {pmid41872889,
year = {2026},
author = {Merikle, E and Presnall, C and Feaster, T and Moxon, R and Siemers, E and Kerwin, D and Cline, S},
title = {Elucidating the phase 1 trial experience among study participants following completion of the INTERCEPT-AD study of sabirnetug (ACU193) for early Alzheimer's disease: a qualitative interview study.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-026-09656-w},
pmid = {41872889},
issn = {1745-6215},
abstract = {BACKGROUND: Recruitment and retention remain persistent challenges in Alzheimer's disease (AD) clinical trials, particularly as studies increasingly focus on earlier disease stages and require longer participation and more invasive procedures. Understanding how trial enrollment and participation are experienced is critical to improving acceptability and sustaining engagement. Qualitative interviews conducted alongside clinical trials offer an opportunity to capture participant and study partner perspectives on the trial experience. In INTERCEPT-AD, a phase 1 trial evaluating safety and tolerability of the Aβ oligomer-selective monoclonal antibody sabirnetug (ACU193) among participants with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD), semi-structured qualitative interviews concerning trial experience were conducted with a subset of participants and their study partners.

METHODS: Participant/study partner dyads completed qualitative interviews following the final study visit. A semi-structured interview guide elicited descriptions regarding motivations for participating, enrollment decision-making, and positive and negative aspects of participation. Principles of applied qualitative thematic analysis guided the qualitative analyses. Exploratory analyses examined how factors differ by participant gender.

RESULTS: Twenty-eight participants (64.2% female) and their study partners were interviewed, representing 43% of the trial population (n = 65; 53.8% female). Participants and study partner dyads described varied pathways to trial awareness and enrollment decision-making, including both independent and family-involved decisions. Motivations for participation reflected anticipated personal benefit as well as altruistic goals. While interactions with study staff were viewed positively, dyads reported meaningful burdens related to travel, time commitment, and study procedures, with cognitive testing more frequently described as challenging than invasive procedures. A recurring theme was the desire for clearer communication and greater access to study-related information, including test results and treatment assignment. Exploratory analyses suggested that perceived burden and enrollment decision-making may differ by participant gender.

CONCLUSIONS: Study findings suggest opportunities to enhance the AD trial experience by addressing trial-related burdens and logistical aspects of participation. Exploratory gender analyses yielded additional insight into the patient trial experience but should be further examined along with race/ethnicity and study partner characteristics to enhance clinical study design and execution.},
}

@article {pmid41874070,
year = {2026},
author = {Kebsi, D and Barki, C and Dergaa, I and Gouider, R and Ceylan, Hİ and Maddouri, A and Jemai, A and Elloumi, M and Bragazzi, NL and Boussi Rahmouni, H},
title = {Personalized Hearing Loss Care Using SNOMED CT-Aligned Ontology and Random Forest Machine Learning: A Hybrid Decision-Support Framework.},
journal = {Audiology research},
volume = {16},
number = {2},
pages = {},
doi = {10.3390/audiolres16020037},
pmid = {41874070},
issn = {2039-4330},
abstract = {BACKGROUND: Hearing loss affects over 466 million individuals globally and is recognized as a major risk factor for Alzheimer's disease, yet treatment personalization remains limited due to the complexity and diversity of underlying causes. Current diagnostic and therapeutic approaches lack standardized methods to accurately predict the most appropriate intervention for individual patients. The integration of medical ontologies with machine learning offers a promising solution for enhancing diagnostic accuracy and treatment personalization.

AIM: Our study aimed to (i) develop a Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT)-aligned clinical ontology for hearing loss using Semantic Web Rule Language for automated reasoning; (ii) implement a Random Forest classifier trained on ontology-enriched patient data to classify hearing loss types (conductive, sensorineural, mixed, or normal); and (iii) predict optimal personalized treatments based on laterality, severity, audiometric thresholds, and medical history using real-world patient data.

METHODS: We developed a task ontology using Protégé 5.6.3 with Web Ontology Language (OWL), integrated SNOMED CT terminology alignment, and implemented Semantic Web Rule Language rules executed by the Pellet 2.2.0 reasoner. The framework was trained and evaluated on 3723 adult patients from the 2015-2016 National Health and Nutrition Examination Survey (NHANES) dataset with complete audiometric and clinical data. Random Forest models were developed using an 80-20 train-test split with stratified sampling and five-fold cross-validation. Performance was compared between K-Means clustering-based labeling and ontology-based semantic inference using accuracy, precision, recall, F1-score, and log loss metrics.

RESULTS: The ontology successfully generated semantic labels for all 3723 patients, enabling precise classification of hearing loss types, severity levels, and laterality. The Random Forest model with K-Means clustering achieved a test accuracy of 90.2% with a log loss of 0.2766 and a cross-validation mean accuracy of 91.22% (standard deviation 1.2%). Integration of ontology-based semantic enrichment significantly improved performance, achieving a test accuracy of 92.48% with a cross-validation mean accuracy of 92.80% (standard deviation 0.9%). F1-scores improved across all classes, with mixed hearing loss showing a notable increase from 0.86 to 0.92. Feature importance analysis identified audiometric thresholds, ontology-derived severity labels, and medical history as top predictors, enhancing clinical interpretability.

CONCLUSIONS: This study demonstrates that combining SNOMED CT-aligned ontology with Random Forest classification achieves superior diagnostic accuracy and enables personalized treatment recommendations for hearing loss. The hybrid framework provides clinically interpretable decision support while ensuring semantic interoperability with electronic health records. Multi-institutional validation studies are necessary to assess generalizability across diverse populations before clinical deployment.},
}

@article {pmid41874810,
year = {2026},
author = {Jalalian, S and Weickenmeier, J},
title = {Alzheimer's Disease Accelerates Cerebral Atrophy by Over a Decade Compared to Healthy Aging.},
journal = {Annals of biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41874810},
issn = {1573-9686},
support = {1953323//Directorate for Engineering/ ; U19NS120384/NS/NINDS NIH HHS/United States ; },
abstract = {Brain aging is accompanied by progressive morphological and neurobiological changes, which are significantly accelerated in neurodegenerative diseases, such as Alzheimer's disease. Detecting and differentiating these changes early is crucial for diagnosis, treatment planning, and therapeutic development. In this work, we present a computational multiphysics framework that couples protein biomarker propagation with tissue-level atrophy to distinguish between cognitively normal aging, mild cognitive impairment, and Alzheimer's disease. Our model integrates a network-based simulation of amyloid beta and tau protein spread with a finite element model of brain mechanics to simulate longitudinal brain shape changes over 40 years. Notably, we observe that amyloid beta accumulation precedes tau-driven degeneration by over a decade, aligning with empirical biomarker studies. We also introduce several mechanomarkers which are quantitative metrics of brain morphology such as displacement, cortical thickness, curvature, and sulcal depth. They serve as quantitative measures of disease-specific deformation patterns. Our simulations predict that Alzheimer's disease accelerates cerebral atrophy by about 12 years relative to normal aging, with early divergence in medial temporal and occipital regions. Our findings identify cortical thickness and area stretch as early and sensitive markers to distinguish between healthy and abnormal aging. Spatially, the supramarginal gyrus and entorhinal cortex should be considered as regions of early vulnerability. These results underscore the potential of physics-informed computational models to improve early detection of neurodegeneration and guide the development of region- and stage-specific diagnostic tools.},
}

@article {pmid41875305,
year = {2026},
author = {Betat, A and Santos, VD and Oliveira, CGA and Alflen, L and Ferreira, CF and Izídio, GS and Lataro, RM},
title = {Does hypercholesterolemia worsen cognitive decline in arterial hypertension? Insights from clinical and experimental studies.},
journal = {Journal of hypertension},
volume = {},
number = {},
pages = {},
doi = {10.1097/HJH.0000000000004277},
pmid = {41875305},
issn = {1473-5598},
abstract = {BACKGROUND: Arterial hypertension has been linked to cognitive decline, potentially through cerebrovascular alterations and associations with Alzheimer's disease. A positive correlation between elevated serum cholesterol levels and cognitive impairment has been observed. However, the impact of hypercholesterolemia on cognitive decline in both hypertensive rats and patients remains unclear. This study aimed to test the hypothesis that hypercholesterolemia exacerbates cognitive decline in hypertensive rats and human patients.

METHODS: Spontaneously hypertensive rats (SHR) with diet-induced hypercholesterolemia underwent behavioral testing to assess recognition, spatial, and working memory. In patients with stage 2 hypertension, cognitive function was assessed using the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) instruments.

RESULTS: In SHRs, hypercholesterolemia did not alter cognitive performance. Treatment of SHR with amlodipine or captopril decreased arterial pressure; however, this reduction did not improve cognition performance. The MMSE and MoCA, respectively, revealed cognitive impairment in 87.1 and 97.6% of the hypertensive patients. Nevertheless, no significant differences were found in the mean scores between hypertensive patients with and without hypercholesterolemia. No significant correlation was observed between cognitive scores and the use of antihypertensive or lipid-lowering agents.

CONCLUSION: These observations provide evidence that hypercholesterolemia does not exacerbate cognitive impairment in hypertension. Furthermore, our current findings support the hypothesis that antihypertensive treatment, in the absence of strict blood pressure control, may be insufficient to prevent hypertension-related cognitive decline.},
}

@article {pmid41875318,
year = {2026},
author = {Coca, A and Sánchez, R and Molina de Salazar, DI and Peñaherrera, E and Alcocer, L and Barbosa, E and Grassi, G and Lopez-Jaramillo, P and Lurbe, E and Parra-Carrillo, J and Ramirez, AJ and Redón, J and Sebba-Barroso, W and Acosta, A and Aristizábal, D and Bryce, A and Cerezo, G and Cohen, RV and Diaz-Velasco, ME and Hernández, R and Lanas, F and Machado, L and Musso, C and Piskorz, D and Ponte-Negreti, CI and Ramos, O and Sánchez, MJ and Valdez, O and Vicario, A and Villar, R and Parati, G and Whelton, PK and Wyss, F and Mancia, G},
title = {2026 Latin American consensus for the management of patients with hypertension and cardio-renal and metabolic disturbances: endorsed by the Latin American Society of Hypertension, the Iberoamerican Hypertension League, and the World Hypertension League.},
journal = {Journal of hypertension},
volume = {},
number = {},
pages = {},
doi = {10.1097/HJH.0000000000004290},
pmid = {41875318},
issn = {1473-5598},
abstract = {Hypertension is the main risk factor for cardiovascular disease (CVD), affecting 20-40% of Latin American (LATAM) adults, and responsible for more than two million deaths annually due to CVD. The different ethnic, economic, geographic, and cultural characteristics of the LATAM population influence the high prevalence of all cardiovascular risk factors (CVRF), particularly metabolic disturbances such as type 2 diabetes (DM2), obesity and the metabolic syndrome. Their main determinants in LATAM includes environment, food quality, social inequity, low education, political aspects, contextual behaviour, and genetics. The prevalence of overweight and obesity in LATAM increased during the last four decades reaching figures of 10-20% in childhood, 30-40% in adolescence, and 60-70% in adults. Many studies in the region have reported the extremely low rates of awareness, treatment, and control of CVRF in the general population of LATAM, particularly in patients with metabolic disorders, and the consequent high cardiovascular morbidity and mortality. This 2026 LATAM consensus is developed by a large group of experts from different LATAM countries, the USA and Europe, representing areas of internal medicine, cardiology, nephrology, endocrinology, geriatrics, paediatrics, pharmacology, and epidemiology. A careful search for novel studies in LATAM, together with new evidence that has emerged since the 2019 LATAM consensus, support the statements and recommendations in the current report. This update aims to provide clear and useful recommendations for health professionals to improve awareness, treatment, and control of hypertension and associated CVRF in the region.},
}

@article {pmid41875607,
year = {2026},
author = {Negi, M and Amulya, E and Phatale, V and Kumar, R and Srivastava, S},
title = {Nose-to-brain delivery of berberine-loaded nanoemulsion: Amelioration of brain targeting, behavioral, pharmacokinetic, and biodistribution insights for Alzheimer's intervention.},
journal = {Biomaterials advances},
volume = {184},
number = {},
pages = {214835},
doi = {10.1016/j.bioadv.2026.214835},
pmid = {41875607},
issn = {2772-9508},
abstract = {Berberine (BER), a benzylisoquinoline alkaloid, has garnered attention for its multifaceted pharmacological properties, including pronounced antioxidant, anti-inflammatory, and neuroprotective effects. Despite its therapeutic potential in neurodegenerative disorders, including Parkinson's disease, cerebral ischemia, and epilepsy, its clinical translation in Alzheimer's disease (AD) is hindered by poor aqueous solubility, limited systemic bioavailability, and restricted blood-brain barrier (BBB) permeability. This study aimed to overcome these limitations by formulating a BER-loaded nanoemulsion (BER-NE) for intranasal (IN) delivery to achieve direct nose-to-brain (N2B) targeting. The optimized NE exhibited a droplet size of 138.5 ± 0.96 nm and a polydispersity index (PDI) of 0.203 ± 0.007, indicating a monodisperse system. The BER-NE demonstrated a drug content of 99.62 ± 1.02%, confirming efficient drug incorporation. In vitro studies on SH-SY5Y neuroblastoma cells demonstrated that BER-NE reduced reactive oxygen species (ROS) levels by 2.09-fold and restored mitochondrial membrane potential (MMP) with a 3.61-fold increase in red/green fluorescence intensity compared to SCOP-induced cells. Further, pharmacokinetic (PK) profiling revealed that IN BER-NE achieved a 3.2- and 3.6-fold increase in brain Cmax compared to BER-SUS IN and BER-NE IV, respectively. The IN BER-NE demonstrated a 1.7- and 1.9-fold increase in %DTE and %DTP compared to the IN SUS, which supports the efficient N2B delivery. Behavioral assessments demonstrated dose-dependent reversal of SCOP-induced cognitive, depressive, and motor impairments. Additionally, treatment with HD BER-NE and MD BER-NE via the IN route markedly reduced the nitrite accumulation by 4.3- and 3.5-fold compared to the SCOP group, indicating attenuation of nitrosative stress. Collectively, these findings underscore the potential of IN BER-NE as a targeted and non-invasive therapeutic strategy for the management of AD.},
}

@article {pmid41876051,
year = {2026},
author = {Chu, AJ and Erlandsson, A and Williams, JM},
title = {Amyloid precursor protein derivatives differentially alter the microRNA cargo of astrocyte-derived extracellular vesicles.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.03.036},
pmid = {41876051},
issn = {1873-7544},
abstract = {Alterations to the protein and microRNA cargo of extracellular vesicles (EVs) occur in Alzheimer's disease (AD) and may contribute to disease progression. We previously showed that ingestion of amyloid-beta (Aβ) by both murine and human astrocytes leads to alterations to the protein cargo of EVs that induce significant neuronal impairment and apoptosis. Here, we hypothesised that pathological changes to the microRNA cargo of astrocyte-derived EVs (ADEVs) would also occur following exposure of astrocytes to Aβ, whereas treatment of astrocytes with the neuroprotective protein secreted amyloid precursor protein-alpha (sAPPα) would induce neuroprotective changes in microRNA expression in ADEVs. Primary murine astrocytes were treated with vehicle, 0.1 μM Aβ protofibrils (AβPF), 1 nM sAPPα, or 1 nM sAPPα in conjunction with 0.1 μM AβPF (sAPPα + AβPF). Differentially expressed microRNA in ADEVs were detected by RT-qPCR using highly sensitive TaqMan Advanced microRNA arrays representing 168 neurodegeneration-associated microRNA. ADEVs from AβPF-exposed astrocytes contained significantly higher amounts of let-7c-5p, miR-29a-3p and miR-34a-5p, while miR-99b-5p and miR-181d-5p were significantly increased in ADEVs from sAPPα- and sAPPα + AβPF-treated astrocytes, respectively. Bioinformatic analysis revealed that gene targets of microRNA upregulated in ADEVs following astrocytic exposure to either AβPF or sAPPα + AβPF were enriched in numerous pathways with known links to AD pathology, with gene targets of the sAPPα + AβPF group also enriched in immune system-related pathways. In contrast, gene targets of miR-99b-5p are known to directly target pathways that are involved in AD, suggesting that ADEVs secreted by sAPPα-treated astrocytes have neuroprotective potential.},
}

@article {pmid41866337,
year = {2026},
author = {Lindbohm, JV and Stražar, M and Lee, HM and Ashenberg, O and Mars, N and Sipilä, PN and Ripatti, S and Graham, D and Kivimäki, M and Xavier, RJ},
title = {Population and single-cell analyses reveal immune cell-specific expression profiles associated with Alzheimer's disease risk.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71282},
doi = {10.1002/alz.71282},
pmid = {41866337},
issn = {1552-5279},
support = {339568//Research Council of Finland/ ; 350426//Research Council of Finland/ ; 331671//Research Council of Finland/ ; 355567//Research Council of Finland/ ; //Päivikki and Sakari Sohlberg foundation/ ; 221854/Z/20/Z/WT_/Wellcome Trust/United Kingdom ; R01AG056477/AG/NIA NIH HHS/United States ; MR/R024227/1/MRC_/Medical Research Council/United Kingdom ; MR/Y014154/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/genetics/immunology ; Genome-Wide Association Study ; Single-Cell Analysis ; Brain/immunology/metabolism ; Mendelian Randomization Analysis ; Transcriptome ; Genetic Predisposition to Disease ; Quantitative Trait Loci ; },
abstract = {INTRODUCTION: Dysregulation of the peripheral immune system may increase Alzheimer's disease (AD) risk, but the underlying cell type-specific mechanisms remain unclear.

METHODS: We conducted Mendelian randomization and colocalization analyses of 4489 genes using single-cell expression quantitative trait locus data from unstimulated and stimulated peripheral immune cells, integrated with an AD genome-wide association study (N = 455,258). Spatial transcriptomics of brain tissue samples was used to identify brain-infiltrating immune cells.

RESULTS: Thirteen genes were associated with AD risk. Expression of BIN1, CTSW, CTSH, HLA-DRB1, TSTD1, PLEKHA1, and SCIMP increased AD risk, while EPHA1-AS1, FCER1G, FIBP, KAT8, STX4, and HLA-DQA1 reduced it. These associations were peripheral immune cell type and state specific. PLEKHA1 and TSTD1 were upregulated and FIBP downregulated in natural killer and T cells in AD brain tissue.

DISCUSSION: These findings link immune cell-specific gene expression to AD risk across activation states and within brain-infiltrating immune cells, highlighting potential targets for immune-based AD prevention and treatment.},
}

Humans
*Alzheimer Disease/genetics/immunology
Genome-Wide Association Study
Single-Cell Analysis
Brain/immunology/metabolism
Mendelian Randomization Analysis
Transcriptome
Genetic Predisposition to Disease
Quantitative Trait Loci

@article {pmid41867210,
year = {2026},
author = {Choi, JJ and Engelman, CD and Lu, T},
title = {Multi-Omics Integration of Transcriptomics and Metabolomics with Machine Learning Uncovers Novel Risk Factors for Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.28.26347204},
pmid = {41867210},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, memory impairment, and functional deterioration. Its complex pathogenesis involves factors such as amyloid plaques, tau tangles, neuroinflammation, and synaptic dysfunction, but the precise mechanisms remain unclear, hindering effective treatment. Genetic, environmental, and lifestyle factors contribute to AD risk, yet their interactions are poorly understood. Recent advances in transcriptomics and metabolomics have shed light on the molecular underpinnings of AD, with gene expression alterations and metabolic disruptions implicated in disease progression. These multi-omics disruptions highlight the need for integrative analytical approaches to better characterize AD-relevant biology and advance biomarker discovery.

OBJECTIVES: To integrate genetically imputed whole blood transcriptomics and plasma metabolomics to predict cognitive performance (PACC3) and to identify risk genes and metabolites contributing to prediction, thereby characterizing molecular signatures associated with cognitive performance in AD.

METHODS: This study applies a machine learning algorithm to integrate genetically imputed whole blood transcriptomics and measured plasma metabolomics data to predict cognitive performance, as measured by PACC3 score, using data from the Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (N = 1,046). After training a machine learning model on WRAP, the predictive performance was evaluated using an independent dataset from the Wisconsin Alzheimer's Disease Research Center (ADRC) cohort (N = 85). Feature importance was assessed to identify genes and metabolites that may play a role as potential risk factors in AD.

RESULTS: The machine learning model achieved a normalized root mean squared error (NRMSE) of 0.743 ± 0.037 and an R² of 0.311 ± 0.016 across 5-fold holdout test folds in WRAP (p = 5.93 × 10 [-30]), and an NRMSE of 0.915 and an R² of 0.061 when applied to the Wisconsin ADRC cohort. Feature importance revealed transcriptomic biomarkers such as RIPK1 , IL6ST , and BIN1 whose higher imputed expression levels were associated with poorer cognitive performance whereas other potential biomarkers including UGP2 , NDUFB5 , and TMOD2 were associated with better cognitive performance, reflecting mitochondrial energy metabolism and molecular processes associated with cognitive resilience. Several predictive metabolites including benzoate, 3-phenylpropionate, and imidazolelactate also mapped to AD vulnerability signatures, while acyl-carnitine species such as hexanoylcarnitine (C6) and propionate-related metabolites aligned with metabolic resilience.

CONCLUSION: Integrated analysis of transcriptomics and metabolomics demonstrated potential utility for identifying candidate biomarkers associated with cognition in AD. Genes and metabolites reflecting inflammatory signaling, mitochondrial dysregulation, and lipid metabolism emerged consistently among the most influential contributors. These findings align with well-established AD vulnerability pathways and highlight convergent biology across two omics layers. Collectively, this supports the value of multi-omics integration for improving molecular characterization of AD and advancing biomarker prioritization for future mechanistic and translational studies.},
}

@article {pmid41867700,
year = {2026},
author = {Wu, C and Wu, C and Yin, X and Zhong, C},
title = {Serum Homocysteine as a Potential Dynamic Biomarker for Staging and Monitoring Progression in Alzheimer's Disease.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {553269},
pmid = {41867700},
issn = {1176-6328},
abstract = {BACKGROUND: Reliable biomarkers are urgently needed for the early diagnosis and dynamic monitoring of Alzheimer's disease (AD). Serum homocysteine (Hcy) has been increasingly investigated but with inconsistent association to AD severity.

OBJECTIVE: To investigate the correlation between serum Hcy levels and AD severity/cognitive function, and to evaluate its clinical utility as a dynamic monitoring indicator for the disease.

METHODS: This retrospective study enrolled 80 AD patients (stratified by Mini-Mental State Examination [MMSE] score: 40 mild, 28 moderate, 12 severe) and 80 healthy controls from the Cerebrovascular Disease outpatient and inpatient departments of our hospital between January 2022 and December 2024. Fasting serum Hcy was measured via chemiluminescent immunoassay. Correlation with cognitive scores and severity discrimination were analyzed.

RESULTS: Serum Hcy levels were significantly higher in the AD group than controls (21.2 ± 6.6 vs 14.5 ± 4.8 μmol/L, p < 0.05), increasing with severity (mild: 16.8 ± 3.2, moderate: 21.2 ± 4.5, severe: 25.6 ± 5.8 μmol/L, p < 0.001). A strong inverse correlation with MoCA scores was observed (r = -0.76, p < 0.01). ROC analysis showed an AUC of 0.87 for discriminating AD severity, with an optimal cut-off of 17.5 μmol/L (sensitivity 78%, specificity 72%). After 6 months of B-vitamin intervention, Hcy decreased significantly with cognitive improvement.

CONCLUSION: Serum Hcy correlates strongly with AD severity and cognitive decline, supporting its potential as a dynamic biomarker for monitoring progression and treatment response.},
}

@article {pmid41867862,
year = {2026},
author = {Bathini, P and Schilling, S and Rahfeld, JU and Holtzman, DM and Saido, TC and Lemere, CA},
title = {Early Binding of Anti-Amyloid Antibodies to CAA Drives Complement Activation, Inflammation and ARIA in Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.04.709591},
pmid = {41867862},
issn = {2692-8205},
abstract = {Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.},
}

@article {pmid41868184,
year = {2026},
author = {Liu, Z and Zhang, H and Wan, B and Yin, S and Yue, R},
title = {Advances and Therapeutic Potential of Anthraquinone Compounds in Neurodegenerative Diseases: A Comprehensive Review.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {580330},
pmid = {41868184},
issn = {1177-8881},
mesh = {Humans ; *Anthraquinones/pharmacology/chemistry/isolation & purification/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; Animals ; Rheum/chemistry ; },
abstract = {BACKGROUND: Rhubarb, traditionally used in China for neurological disorders, has recently attracted considerable scientific attention for its neuroprotective and cerebrovascular benefits. The main therapeutic components of rhubarb are anthraquinones, including emodin, aloe-emodin, chrysophanol, rhein, and physcion. Accumulating experimental evidence indicates that anthraquinones are of importance in neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, as a promising candidate for drug development, the mechanisms by which anthraquinones treat NDDs have not been systematically reviewed. Therefore, this article outlines the anti-neurodegenerative effects of anthraquinones, focusing on their molecular mechanisms.

OBJECTIVE: This article reviews recent research progress of anthraquinones in NDDs, focusing on their potential targets and pathways to provide new ideas for the intervention and treatment of NDDs.

METHODS: A comprehensive search of PubMed, Web of Science, and Google Scholar was conducted for articles on the intervention of anthraquinones in NDDs in the past 20 years. The collected information was then summarized and analyzed.

RESULTS: Anthraquinones ameliorate NDDs through multiple mechanisms. They exhibit antioxidant and anti-inflammatory effects, protect mitochondria, and regulate microglial polarization. Furthermore, anthraquinones inhibit pyroptosis, apoptosis, tau phosphorylation, Aβ/α-synuclein aggregation, and acetylcholinesterase activity, while restoring metal homeostasis, activating estrogen receptors, modulating gut microbiota, increasing BDNF levels, and preserving blood-brain barrier permeability. More notably, these compounds play a neuroprotective role by mediating multiple signaling pathways and targets, including Nrf2, ERK1/2, PI3K/mTOR, ROS/TXNIP, SIRT1/PCG-1α, NLRP3, PI3K/Akt, MAPK, TLR4-NFκB, CaM/CaMKIV, and Ca[2+]/EGFR/PLCγ.

CONCLUSION: The pleiotropic actions of anthraquinones highlight their potential as therapeutic candidates for NDDs, yet clinical validation remains essential. Future studies should emphasize rigorously designed clinical trials and optimized brain-targeted delivery platforms. This review consolidates current evidence to support their translational development.},
}

Humans
*Anthraquinones/pharmacology/chemistry/isolation & purification/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/pharmacology/chemistry/isolation & purification
Animals
Rheum/chemistry

@article {pmid41870677,
year = {2026},
author = {Some, A and Naskar, N and Thomas, DM and Jeengar, MK and Nassar, A},
title = {Senescence as a Central Node in Alzheimer's Disease: Molecular Triggers, Cellular Effectors, and RNA-Based Interventions.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41870677},
issn = {1573-6903},
mesh = {*Alzheimer Disease/metabolism/pathology/therapy ; Humans ; Animals ; *Cellular Senescence/physiology ; Brain/metabolism/pathology ; Oxidative Stress/physiology ; },
abstract = {Alzheimer's disease (AD) is the most frequent neurodegenerative disorder. It is characterized by the buildup of amyloid-β (Aβ) plaques, as well as of tangles made out of tau that increasingly damage and kill neurons while also impairing memory and thinking. Recent findings indicate that cellular senescence is implicated in the pathogenesis of AD. Senescence occurs when cells irreversibly stop dividing under stress. In the brain, it can be induced by chronic activation of astrocytes and microglia, Aβ toxicity, tau hyperphosphorylation and oxidative stress. Senescent cells secrete proinflammatory factors, i.e., the senescence-associated secretory phenotype (SASP). These molecules promote inflammation, destroy mitochondria and interfere with synapses in ways that speed up the progress of the disease. Blocking those senescent cells may offer a new approach to treatment. Approaches including VEGFR-1 and SIRT5 interference, senolytics or senomorphs drugs, NLRP3 antagonist, PAI-1 inhibitors and small vessels inhibitors (including aspirin, curcumin derivatives and sildenafil) have been suggested to promisingly mitigate brain injury. RNA based therapy (miRNAs- and lncRNAs-targeted) and exosomal derived biomarkers are also an optimistic approach. A clearer understanding of how senescence is implicated in AD would have implications regarding the design and application of novel treatments aimed at delaying disease onset, slowing down progression or preserving brain function.},
}

*Alzheimer Disease/metabolism/pathology/therapy
Humans
Animals
*Cellular Senescence/physiology
Brain/metabolism/pathology
Oxidative Stress/physiology

@article {pmid41870774,
year = {2026},
author = {Mahmoud, MH and Mjery, Y and Fatani, SH and Jan, A and Taymour, S and Abdelsalam, K and Nasif, WA and Mukhtar, MH and Eldein, MMN},
title = {Protective effects of watercress (Nasturtium officinale) leaf methanolic extract against dextran sodium sulfate induced colon inflammation in rats.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41870774},
issn = {1568-5608},
abstract = {Numerous factors can lead to inflammation and enlargement of the colon, posing a serious health risk. This study investigated the protective effects of watercress (Nasturtium officinale) leaf methanolic extract against dextran sodium sulfate (DSS)-induced colonic inflammation in rats. Phytochemical analysis showed high levels of polyphenols, flavonoids, and condensed tannins in the methanolic extract, which exhibited the strongest in vitro anti-diabetic (α-amylase and α-glucosidase enzymes; Inhib. % 72.61 and 62.36%, respectively), anti-Alzheimer (AChE; Inhib. % 65.86 ± 0.15%), and anti-arthritic activity (protein denaturation and the proteinase enzyme activity; Inhib. % 58.09 ± 0.14 and 55.39 ± 0.14%, respectively) and was therefore selected for the in vivo study. Oxidative stress and inflammatory responses in colon tissue were evaluated using biochemical tests, histopathological examination, and assessment of mRNA levels of inflammatory markers (NF-κB, IL-6, IL-1β) and antioxidant enzymes (SOD1, CAT, GPx1). Watercress extract treatment successfully reinstated antioxidant enzyme activity and decreased inflammatory indicators in both pre-treated and post-treated cohorts. Histopathological examinations demonstrated a significant enhancement in the architecture of colon tissue and a decrease in inflammatory lesions. Molecular assays confirmed normalization of mRNA expression of antioxidant enzymes and inflammatory markers disrupted by DSS administration (p ≤ 0.05). These findings indicate that the methanolic extract of watercress leaves exerts protective effects against DSS-induced colonic inflammation at biochemical, histological, and molecular levels, supporting its potential as a natural anti-inflammatory agent.},
}

@article {pmid41870813,
year = {2026},
author = {Upadhayay, S},
title = {Role of Pentacyclic Triterpenes in the Management of Neurological Disorders: An Insight into Molecular Mechanisms and Therapeutic Approaches.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41870813},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; *Pentacyclic Triterpenes/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Neurological disorders represent major public health concerns globally, as they profoundly affect motor function, memory, and cognitive abilities, thus compromising patients' independence and quality of life. Despite extensive research, current treatment approaches predominantly offer palliative care, failing to hinder disease progression. The rising incidence of these disorders underscores an urgent necessity for more efficacious and disease-modifying therapies. According to findings, pentacyclic triterpenoids exhibit neuroprotective properties by inhibiting neuronal oxidative stress, neuroinflammation, apoptosis, and degeneration, making them promising candidates for targeting the underlying causes of neurodegeneration. Therefore, in this review, we explore natural and synthetic pentacyclic triterpenoids that exhibit neuroprotective effects by modulating signaling pathways, such as HMGB1, TLR4, NLRP3, NF-κB, Nrf2, PI3K, Akt, and CREB, which play crucial roles in regulating cell proliferation, differentiation, and neuronal plasticity. The present literature survey is performed by searching various keywords with several combinations: "pentacyclic triterpenes", "neurological disorders", Parkinson's Disease", "Huntington's Disease", "Alzheimer's Disease", "Multiple sclerosis", "Amyotrophic Lateral Sclerosis" "Epilepsy", "mitochondria dysfunction", "oxidative stress", "preclinical studies", "molecular mechanisms", and "clinical studies". Studies indicates that pentacyclic triterpenoids have a wide range of therapeutic potentials, current findings summarizes existing knowledge and examines the neuroprotective properties and potential molecular mechanisms of pentacyclic triterpenoids related with health benefits and neurological diseases. Available evidence suggests that pentacyclic triterpenoids possess the capacity to impede disease progression and may be beneficial in the treatment of neurological disorders. This review strengthens the understanding of pentacyclic triterpenoids and their molecular mechanisms, while also facilitating pharmaceutical discovery and development for neurodegenerative disorders.},
}

Humans
Animals
*Nervous System Diseases/drug therapy/metabolism
*Pentacyclic Triterpenes/therapeutic use/pharmacology
*Neuroprotective Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Oxidative Stress/drug effects

@article {pmid41870902,
year = {2026},
author = {Kang, J and Du, X and Zhang, X and Li, Y and Wang, C and Sun, S},
title = {METTL3-mediated TIGAR m6A modification and its role in microglia activation related to Alzheimer's disease.},
journal = {Neuroreport},
volume = {37},
number = {5},
pages = {195-203},
doi = {10.1097/WNR.0000000000002253},
pmid = {41870902},
issn = {1473-558X},
mesh = {Humans ; *Microglia/metabolism ; *Alzheimer Disease/metabolism ; *Methyltransferases/metabolism/genetics ; *Apoptosis Regulatory Proteins/metabolism ; *Adenosine/analogs & derivatives/metabolism ; Amyloid beta-Peptides/pharmacology ; Cell Line ; Phosphoric Monoester Hydrolases ; },
abstract = {OBJECTIVE: This study focused on clarifying whether methyltransferase3 (METTL3) participates in the polarization and activation of microglia in Alzheimer's disease (AD) by mediating the N6-methyladenosine (m6A) modification level of TP53-induced glycolysis and apoptosis regulator (TIGAR).

METHODS: Human microglia HMC3 cells were transfected with overexpression or knockdown lentivirus of METTL3, TIGAR, or TIGAR before being induced by Aβ treatment to establish an in-vitro AD cell model. The expression of TIGAR and METTL3 was measured by real-time quantitative PCR and western blot. Microglial polarization was assessed by detecting the expression of M1 microglia marker CD86 and M2 marker CD206 using immunofluorescence and measuring the protein expression of M1-associated iNOS and IL-1β, and M2-associated Arg-1 and IL-10 using western blot. PAR-CLIP was employed to examine the binding of METTL3 to TIGAR mRNA, and MeRIP was used to measure the m6A level of TIGAR mRNA. The stability of TIGAR mRNA was evaluated by an actinomycin D assay.

RESULTS: In Aβ-induced HMC3 cells, both METTL3 and TIGAR expressions were reduced. Aβ treatment in HMC3 cells increased M1 polarization and decreased M2 polarization. But this effect was partially reversed by overexpression of either METTL3 or TIGAR. METTL3 binds to TIGAR mRNA and increases its m6A level, thereby promoting TIGAR mRNA stability.

CONCLUSION: METTL3 modulates the balance of Aβ-induced polarization and microglia activation in HMC3 cells by upregulating TIGAR, promoting polarization toward an anti-inflammatory profile.},
}

Humans
*Microglia/metabolism
*Alzheimer Disease/metabolism
*Methyltransferases/metabolism/genetics
*Apoptosis Regulatory Proteins/metabolism
*Adenosine/analogs & derivatives/metabolism
Amyloid beta-Peptides/pharmacology
Cell Line
Phosphoric Monoester Hydrolases

@article {pmid41863079,
year = {2026},
author = {Li, J and Guo, L and Cai, W and Mei, J and Liu, J and Liu, Y},
title = {Overcoming the blood‒brain barrier: nanomedicine strategies for targeted delivery and multimodal therapy in Alzheimer's disease.},
journal = {Drug delivery},
volume = {33},
number = {1},
pages = {2645830},
doi = {10.1080/10717544.2026.2645830},
pmid = {41863079},
issn = {1521-0464},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Nanomedicine/methods ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles/chemistry ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System ; Combined Modality Therapy ; },
abstract = {Alzheimer's disease (AD) remains a significant therapeutic challenge, primarily because the formidable blood‒brain barrier (BBB), which drastically limits the brain bioavailability of most drugs. Nanoparticle-based drug delivery systems offer a promising strategy to overcome this central obstacle. This review systematically examines the design, mechanisms, and applications of nanomedicine in AD therapy. We analyze key strategies for enhancing BBB penetration through surface engineering and the utilization of various nanocarriers, including liposomes, exosomes, dendrimers, and carbon dots. Furthermore, we discuss how stimuli-responsive release mechanisms (e.g. responsive to pH, enzymes, reactive oxygen species, light, or ultrasound) enable targeted and precise drug delivery. A critical focus is placed on how these multifunctional nanoplatforms can address multiple AD pathogenic pathways simultaneously, such as amyloid-β and tau aggregation, cholinergic dysfunction, oxidative stress, neuroinflammation, and gut‒brain axis dysregulation. Although preclinical evidence is compelling, the clinical translation of these nanotherapies is hindered by challenges related to long-term biocompatibility, scalable manufacturing, patient heterogeneity, and regulatory frameworks. This review highlights the translational potential of nanomedicine in AD treatment while outlining the key hurdles that must be addressed for its successful implementation.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Blood-Brain Barrier/metabolism/drug effects
*Nanomedicine/methods
Animals
*Drug Delivery Systems/methods
Nanoparticles/chemistry
Drug Carriers/chemistry
Nanoparticle Drug Delivery System
Combined Modality Therapy

@article {pmid41863272,
year = {2026},
author = {Liang, Y and Li, M and Zhang, L and Zhu, R and He, X and Wei, Z},
title = {Akkermansia muciniphila in Central Nervous System Disorders: Mechanisms, Controversies, and Therapeutic Potential.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419923251231071255},
pmid = {41863272},
issn = {1875-6190},
abstract = {Akkermansia muciniphila (A. muciniphila) is an intestinal mucus-dwelling mucindegrading bacterium that has recently attracted great interest due to its involvement in several metabolic diseases, including obesity, diabetes, and non-alcoholic fatty liver disease. Recent findings have indicated that A. muciniphila plays an important role in central nervous system (CNS) disorders via the microbiota-gut-brain axis (MGBA). This review highlights its dual roles in neuroprotection and pathogenesis, focusing on three key mechanisms, including immunomodulation, metabolic regulation, and barrier reinforcement. Although A. muciniphila has a beneficial role in the treatment of Alzheimer's disease, stroke, and depression, it is controversial for multiple sclerosis and Parkinson's disease because of context-dependent effects. We herein summarize recent progress in an understanding of the complex interplay between A. muciniphila and CNS disorders, highlighting that more work is needed to elucidate this relationship's causality and applicability toward treatment. Finally, we discuss the potential of A. muciniphila as a diagnostic biomarker and a target for nextgeneration probiotics in CNS disease management.},
}

@article {pmid41863273,
year = {2026},
author = {Singh, DD},
title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438970260115164001},
pmid = {41863273},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.},
}

@article {pmid41863402,
year = {2026},
author = {van Rooij, JR and Vasilkovska, T and Van Spilbeeck, I and Van Audekerke, J and Kosten, L and Bertoglio, D and Verhoye, M},
title = {Resveratrol supplementation and caloric restriction exert sex-specific effects on cerebrovascular function in a rat model of Alzheimer's Disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261433498},
doi = {10.1177/0271678X261433498},
pmid = {41863402},
issn = {1559-7016},
abstract = {Cerebrovascular dysfunction, including reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), contributes to Alzheimer's disease (AD). Caloric restriction (CR) and resveratrol (Rsv) benefit vascular health, yet their impact on CBF and CVR in AD remains unclear. Here, we investigated the cerebrovascular effects of 40% CR or Rsv supplementation in WT and TgF344-AD rats. Using pseudo-continuous arterial spin labelling (pCASL) MRI, we observed that male Tg control (Ctrl) rats exhibited reduced relative CBF (rCBF) and absolute CBF (aCBF) in the caudate-putamen at baseline compared to WT Ctrl and Tg Rsv rats, while Rsv restored CBF to WT levels. Male Rsv rats also showed higher rCBF than CR rats in the somatosensory cortex, irrespective of genotype. In the cingulate cortex, male Tg rats had lower rCBF than WT, irrespective of treatment. During hypercapnia, Tg males displayed lower rCBF and aCBF across multiple regions, while Rsv increased rCBF in cingulate cortex and somatosensory cortex, regardless of genotype. In females, treatments did not affect baseline or hypercapnic CBF, although CR and Rsv reduced CVR compared to Ctrl. In summary, these findings suggest Rsv reverses AD-related hypoperfusion in males, whereas CR may impair cerebrovascular responsiveness in females, highlighting the need for sex-specific therapeutic strategies.},
}

@article {pmid41863469,
year = {2026},
author = {Qi, F and Chen, H and Li, S and Zhang, Y and Chen, X and Wang, A},
title = {From Mechanism to Therapy: Isoliquiritigenin as a Novel Anti-Inflammatory Agent for Inflammatory Disease Management.},
journal = {Endocrine, metabolic & immune disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715303395815250904075148},
pmid = {41863469},
issn = {2212-3873},
abstract = {INTRODUCTION: Accumulating evidence has multilaterally proved the indispensable contribution of inflammation in mediating various diseases over the last decade, including sepsis, obesity, diabetes, and neurological disorders. This established correlation between inflammation and disease progression has positioned anti-inflammatory intervention as a promising therapeutic strategy for disease prevention and treatment. Naturally occurring flavonoids have emerged as a subject of extensive investigation due to their well-documented anti-inflammatory properties and molecular mechanisms. The current review provides a comprehensive analysis of isoliquiritigenin (ISL), a bioactive flavonoid compound isolated from Glycyrrhiza glabra (licorice), with particular emphasis on its pharmacological activities and molecular mechanisms in modulating inflammation- associated disorders.

METHODS: A systematic literature review was executed across the PubMed and Google Scholar electronic databases spanning the period from January 2000 to December 2024, employing the following keyword combination: "isoliquiritigenin" (MeSH) AND "inflammation" (MeSH).

RESULTS: ISL was found to exhibit significant therapeutic potential in mitigating both acute and chronic inflammatory responses. Particular attention was devoted to elucidating ISL's multi-target regulatory mechanisms in acute organ injury models, including neurological, pulmonary, hepatic, and renal systems. Furthermore, the compound's therapeutic effects were found to extend to chronic inflammatory pathologies associated with metabolic and neurodegenerative disorders, notably diabetes mellitus, obesity-related complications, and Alzheimer's disease-associated tissue damage, particularly manifesting in ocular, pulmonary, and cardiovascular systems. Systematic characterization of ISL's molecular targets and associated signalling cascades, like MAPK, JAK/STAT3, Nrf2, and SIRT1 pathways, substantially enhanced our mechanistic understanding of its anti-inflammatory properties.

DISCUSSION: ISL demonstrated extensive protection in many inflammatory models. Its multi-target action implied broad therapeutic applicability. However, despite its excellent anti-inflammatory efficacy and safety profile, further study is required to investigate its effectiveness for clinical translation.

CONCLUSION: This comprehensive analysis has provided a pharmacological foundation for developing ISL-based therapeutic interventions against inflammation-driven human pathologies.},
}

@article {pmid41863585,
year = {2026},
author = {Yeh, PY and Liao, RM and Chang, HY and Lin, WT and Chen, YZ and Lane, HY and Lin, CH},
title = {Gender-specific effects of sodium benzoate on cognitive improvement in individuals with dementia: a meta-analysis of randomized controlled trials.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41863585},
issn = {1433-8491},
support = {NHRI-EX113-11133NI//National Health Insurance Administration/ ; NSTC 113-2622-B-039-003//National Science and Technology Council/ ; MOST 111-2314-B-182A-024 -MY3//National Science and Technology Council/ ; DMR-HHC-113-11 and DMR-113-211//China Medical University Hospital/ ; NHRI-EX111-10816NC//National Health Research Institutes/ ; CMRPG8M1311//Chang Gung Memorial Hospital/ ; },
abstract = {BACKGROUND: Previous double-blind randomized controlled trials (RCTs) have shown that sodium benzoate, a D-amino acid oxidase inhibitor enhancing D-serine availability and NMDA receptor-mediated function, is able to improve cognition in patients with cognitive decline. Accordingly, this study aimed to compare cognitive outcomes between patients receiving sodium benzoate and those receiving placebo.

METHODS: Following the PRISMA guidelines, this meta-analytic study utilized appropriate keyword strings to systematically search the PubMed, Embase, and Cochrane databases for RCTs published in all languages from inception to June 2024. Included criteria were: (1) patients aged 50 or older; (2) those diagnosed with dementia (probable Alzheimer's disease or vascular dementia) or those with mild cognitive impairment (MCI) having a clinical dementia rating score of 0.5; (3) RCTs comparing the effect of benzoate treatment with that of placebo controls; and (4) the use of cognitive tests as therapeutic effect outcomes.

RESULTS: Of 351 articles screened, five RCTs were included (246 sodium benzoate, 178 placebo; mean age 72.6 years; mean education 6.01 years; 62% female). The overall effect size for the therapeutic effect of sodium benzoate on cognitive improvement was significant (p = 0.02), with females outperforming males (p = 0.02). Additionally, regression analysis found the cognitive outcome generated from sodium benzoate was not influenced by the use of anti-dementia medication.

CONCLUSION: Our findings highlighted a better understanding of the effect of sodium benzoate on cognitive improvement, particularly in female patients with MCI and dementia.},
}

@article {pmid41863761,
year = {2026},
author = {Bhardwaj, V and Goel, F and Rajput, MS},
title = {Targeting oxidative stress and neurodegeneration: the role of Putranjiva roxburghii in Alzheimer's.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41863761},
issn = {1568-5608},
abstract = {AD is a complex neurodegenerative disease that leads to progressive memory loss, worsening cognitive abilities, and synaptic dysfunction. The pathophysiology of the disease is driven by oxidative stress and neuroinflammation, which cause neuronal damage and may facilitate amyloid-beta aggregation and tau hyperphosphorylation. Current treatment strategies provide symptomatic improvement but do not address the multifactorial causes of the disease; therefore, multi-targeted approaches are critical. Putranjiva roxburghii is a medicinal plant with a wealth of ethnomedicinal literature from India. It contains a variety of phytochemicals, including flavonoids, lignans, glycosides, and triterpenoids, that collectively exhibit antioxidant, anti-inflammatory, and neuroprotective effects. Preclinical studies suggest that it can scavenge ROS, decrease LPO, modulate cholinergic systems, and interfere with amyloid and tau pathology, supporting potential cognitive benefits. Notwithstanding the promising potential of these findings, challenges remain, including variable extraction methods, limited pharmacokinetic information, and the absence of clinical validation, which are obstacles to translation. This manuscript provides a limited examination of the phytochemical profile, neuroprotective mechanisms, and potential therapeutic applications in Alzheimer's disease (AD) attributed to P. roxburghii, and highlights the necessity for standardized formulations, molecular docking methodology, and rigorously designed clinical studies to determine its efficacy and safety in humans.},
}

@article {pmid41864176,
year = {2026},
author = {Li, J and Zhang, H and Zhou, X and Wang, Y and Wei, C and Yan, H and Wang, J},
title = {Molecular insights into SEN177 binding to human glutaminyl cyclase: a combined MD and DFT study.},
journal = {Journal of molecular graphics & modelling},
volume = {145},
number = {},
pages = {109372},
doi = {10.1016/j.jmgm.2026.109372},
pmid = {41864176},
issn = {1873-4243},
abstract = {Aberrant upregulation of human glutaminyl cyclase (hQC) is associated with the onset and progression of neurodegenerative disorders, notably Alzheimer's disease and Huntington's disease. Consequently, inhibition of hQC activity represents a potential avenue for treatment. SEN177, a potent small-molecule hQC inhibitor, has demonstrated notable preclinical efficacy but its binding mechanism remains incompletely understood. Herein, an integrated computational investigation was performed to elucidate the molecular basis of SEN177-hQC recognition. Notably, we implemented an integrated MD-energy decomposition-DFT scheme to rationalize the molecular mechanism of SEN177-hQC recognition. Molecular dynamics simulations indicated that SEN177 binding constrained the intrinsic conformational mobility of hQC, thereby stabilizing the protein-ligand complex. Energy decomposition analyses indicated that the P1 pharmacophore contributed significantly to binding affinity, with key interactions involving hotspot residues D159, E201, E202, W207, and L249. Complementary DFT analyses identified the frontier molecular orbitals and mapped electrophilic and nucleophilic regions that facilitated specific noncovalent contacts. Collectively, these results provide detailed mechanistic insight into the interaction landscape of SEN177 with hQC and provide a conceptual framework for designing more potent and selective hQC-targeting agents.},
}

@article {pmid41864514,
year = {2026},
author = {Wang, B and Cheng, K and Chen, Z and Chen, Y and Wang, Z and Ni, J},
title = {Transcranial Ultrasound Stimulation and Vagus Nerve Stimulation: Potential Therapeutic Strategies for Alzheimer's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111837},
doi = {10.1016/j.brainresbull.2026.111837},
pmid = {41864514},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with limited efficacy from existing medications and conventional neuromodulation therapies. In recent years, emerging neuromodulation techniques have demonstrated promising therapeutic potential. This review focuses on exploring the therapeutic value of transcranial ultrasound stimulation (TUS) and vagus nerve stimulation (VNS) for AD. We systematically review the evidence for these techniques in AD basic research and clinical practice, elucidating their unique mechanisms of action. The review further contrasts the advantages of TUS and VNS over traditional AD therapies and explores their potential for synergistic application with conventional treatments. Finally, we propose future research directions, including combined VNS and TUS treatment strategies based on complementary mechanisms, aiming to provide theoretical foundations for developing multi-targeted, personalized AD therapies.},
}

@article {pmid41864895,
year = {2026},
author = {Na, Y and Bai, J and Zhang, N and Geng, F and Wang, X},
title = {Nanomaterials for Alzheimer's disease: emerging strategies in diagnosis and therapy.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04281-w},
pmid = {41864895},
issn = {1477-3155},
support = {LH2023H050//Heilongjiang Province Natural Science Foundation/ ; LSLSKL 20240105//the Open Research Project of the State Key Laboratory for Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; JT120924080306//Lateral Project of Lunan Pharmaceutical Group Co., Ltd/ ; 22042240002//Lateral Project of Dong'e Ejiao Co., Ltd/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent and progressive neurodegenerative disease characterized by behavioral abnormalities, memory loss, and cognitive decline, presenting significant challenges for early diagnosis and effective treatment. Given the multifactorial pathology of AD and the limited efficacy of conventional approaches, nanotechnology-based strategies have attracted increasing attention as promising solutions to address these unmet clinical needs. Nanomaterials offer distinct advantages for the sensitive and selective detection of AD-related biomarkers due to their high specific surface area, variable surface functions, and capacity to cross biological barriers. This review discusses recent advances in sensing and imaging technologies for AD detection via nanotechnology. Beyond diagnostics, nanomaterials also hold significant therapeutic potential. A variety of nanosystems have been developed to improve drug solubility, promote blood-brain barrier penetration, and achieve controlled or stimulus-responsive drug release. This review presents a comprehensive landscape of recent advances in nano-enabled targeting techniques, with a focus on the target therapy of neuron, microglia, astrocyte, Aβ, Tau, mitochondria and iron. Moreover, the designs of multifunctional nanostructures has enabled synergistic multi-target therapies, which concurrently modulate several pathological pathways. These integrated strategies that integrate antioxidant, anti-inflammatory, anti-aggregative, and neuroprotective mechanisms represent a new paradigm for personalized and precision nanomedicine in AD management.},
}

@article {pmid41865200,
year = {2026},
author = {Leelaprachakul, N and Visitnonthachai, D and Niyomchan, A and Maliphol, K and Watcharasit, P and Satayavivad, J},
title = {Arsenic Promotes Intracellular Aβ(1-42) Accumulation via Enhanced APP but Reduced NEP Expression, and Indirectly Stimulates Extracellular Aβ Aggregation through AChE Induction in Differentiated SH-SY5Y Cells.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41865200},
issn = {1559-0720},
support = {PHD/0207/2559//The Royal Golden Jubilee Ph.D. Program/ ; Grant no. 49892/4778750//Thailand Science Research and Innovation (TSRI)/ ; },
abstract = {Arsenic exposure is associated with Alzheimer's disease (AD) development through unclear mechanisms. This study investigated the effects of arsenic on amyloid-β (Aβ), a peptide linked to AD pathogenesis, in differentiated SH-SY5Y neuroblastoma cells. Arsenic increased intracellular Aβ(1-42) while decreasing its extracellular levels. It elevated amyloid precursor protein (APP) while decreasing a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a non-amyloidogenic secretase, suggesting a shift in APP processing toward an amyloidogenic pathway. Arsenic reduced intracellular neprilysin (NEP), an Aβ-degrading enzyme, while increasing its extracellular levels. Interestingly, Aβ(1-42) detection by immunogold transmission electron microscopy revealed that NEP restoration by humanin G (HNG) reduced arsenic-induced intracellular Aβ(1-42). Thus, the inhibition of NEP moderately contributed to the arsenic-induced intracellular Aβ(1-42). Thioflavin T (ThT) assay revealed that arsenic enhanced extracellular Aβ aggregation. Arsenic upregulated extracellular acetylcholinesterase (AChE), known to promote Aβ aggregation. Co-treatment with HNG, which reportedly prevented AChE-promoted Aβ aggregation, attenuated Aβ aggregation by arsenic. Accordingly, arsenic-elevated AChE possibly promotes extracellular Aβ aggregation. Overall, arsenic promotes intracellular Aβ(1-42) accumulation, possibly through the upregulation of APP and a decrease in the Aβ-degrading enzyme, NEP, and extracellular Aβ aggregation by AChE upregulation. As both Aβ intracellular accumulation and extracellular aggregation play pivotal roles in AD, our findings may provide insightful mechanistic links between arsenic and AD.},
}

@article {pmid41865758,
year = {2026},
author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Feldman, HH},
title = {Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00459-9},
pmid = {41865758},
issn = {1474-547X},
abstract = {BACKGROUND: Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease.

METHODS: evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome.

FINDINGS: Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline. In evoke+, 54 (2·8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group).

INTERPRETATION: Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications.

FUNDING: Novo Nordisk.},
}

@article {pmid41865782,
year = {2026},
author = {Cai, Y and Kang, J and Xie, H and Wu, D},
title = {From mechanisms to clinical applications: Advances in 40 Hz gamma oscillation modulation for the treatment of neurological disorders.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115741},
doi = {10.1016/j.expneurol.2026.115741},
pmid = {41865782},
issn = {1090-2430},
abstract = {This review systematically summarizes the mechanisms of 40 Hz gamma rhythm neuromodulation and its research advances in neurological disorders. As a key rhythm for brain information integration, 40 Hz gamma oscillations are generated by the interaction between excitatory and inhibitory neurons, and play a central role in cognitive functions such as attention and memory. They are commonly characterized by decreased power or loss of synchrony in various diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia, serving as a shared electrophysiological hallmark. Extrinsic 40 Hz stimulation (e.g., transcranial alternating current stimulation, light flickering, acoustic stimulation) can restore endogenous gamma rhythms through the entrainment effect, improve excitation-inhibition balance, enhance synaptic plasticity, and promote the clearance of pathological proteins by activating microglia and other mechanisms. Clinical studies have shown that this technology improves cognitive, emotional, and motor functions, with advantages of non-invasiveness and high safety. Despite challenges such as individual variability, marked methodological heterogeneity (e.g., inconsistent stimulation parameters, small sample sizes, and lack of multicenter randomized controlled trials), and unclear long-term effects, 40 Hz neuromodulation still demonstrates broad therapeutic potential and provides a novel rhythmic intervention strategy for neurological disorders.},
}

@article {pmid41861975,
year = {2026},
author = {Huang, S and Lai, W and Zhao, Y and Pan, K and Xu, H and Lin, S and Liao, M and Liu, X and Lu, P and Wu, Y and Yang, W and Song, P and He, H and Hu, Y and Li, C},
title = {Hypertension, Antihypertensive Treatment, and Memory Decline: Consistent and Divergent Patterns in Aging Populations across Four Countries, 2010-2019.},
journal = {American journal of preventive medicine},
volume = {},
number = {},
pages = {108343},
doi = {10.1016/j.amepre.2026.108343},
pmid = {41861975},
issn = {1873-2607},
abstract = {INTRODUCTION: Memory decline is a hallmark of all-cause dementia. Hypertension, a highly prevalent and modifiable risk factor, is a critical intervention target. Cross-national, long-term studies examining the relationship between hypertension management and 10-year memory decline remain limited.

METHODS: We analyzed 2010-2019 data from four nationally representative aging cohorts. Hypertension (BP ≥140/90 mmHg or antihypertensive medications use) was categorized as treated and untreated. Memory was assessed using immediate and delayed word recall tasks. Linear mixed-effects models evaluated memory trajectories by hypertension and treatment status. Pooled analyses examined cross-country differences. Data analysis occurred from December 2024-January 2026.

RESULTS: Compared with non-hypertensive participants, hypertensive participants had a faster annual decline in the US (-0.010; 95% CI: -0.015, -0.006) and England (-0.011; 95% CI: -0.018, -0.004). Compared with treated hypertensive participants, untreated hypertensive participants had a slower annual decline among hypertensive participants in the US (0.010; 95% CI: 0.003, 0.017), but a faster decline in China (-0.022; 95% CI: -0.034, -0.011). Pooled analyses showed no cross-country differences in the association between hypertension and memory; however, compared with treated hypertension in the US, untreated hypertension was associated with faster memory decline in Mexico (-0.028; 95% CI: -0.051, -0.006) and China (-0.032; 95% CI: -0.045, -0.020).

CONCLUSIONS: Hypertension and treatment status are associated with memory decline in country-specific patterns. These findings highlight hypertension as a key modifiable risk factor and support prevention and treatment to promote cognitive health. Tailored approaches that align with local healthcare systems and population needs are essential.},
}

@article {pmid41856254,
year = {2026},
author = {Lu, S and Qiu, S and Guan, Y and Zhang, A and Zhao, Q},
title = {Tau phosphorylation homeostasis: Mechanisms, targets, and therapeutic implications in Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {118},
number = {},
pages = {103097},
doi = {10.1016/j.arr.2026.103097},
pmid = {41856254},
issn = {1872-9649},
abstract = {Neurofibrillary tangles, composed of excessively phosphorylated tau, are a core neuropathological hallmark of Alzheimer's disease (AD). However, therapeutic strategies aimed at directly clearing neurofibrillary tangles have demonstrated limited clinical efficacy, shifting the research focus towards the fundamental underlying mechanism- the dysregulation of tau phosphorylation. Evidence indicates that tau physiological phosphorylation is indispensable for microtubule stability and normal neuronal function, while its aberrant hyperphosphorylation drives neurodegeneration. Consequently, restoring tau phosphorylation homeostasis, rather than merely eliminating the pathological protein, has emerged as a promising therapeutic paradigm. This review systematically delineates the physiological functions and pathological mechanisms of tau phosphorylation, highlighting its central role in AD pathogenesis. We summarize recent advances in drug development targeting key kinases and phosphatases, and discuss the diagnostic value and application prospects of tau phosphorylation biomarkers. Ultimately, this study aims to provide a theoretical framework for novel precision treatment strategies in AD.},
}

@article {pmid41858175,
year = {2026},
author = {Lin, CH and Wang, SH and Lane, HY},
title = {Sodium benzoate, a D-amino acids oxidase inhibitor, for the treatment of mild cognitive impairment: Pooled data from three randomized, double-blind, placebo-controlled trials.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70052},
pmid = {41858175},
issn = {1440-1819},
support = {DMR-115-102//China Medical University Hospital/ ; CMRPG8M1311//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8M1361//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1201//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1121//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1212//Kaohsiung Chang Gung Memorial Hospital/ ; NHRI-EX111-10816NC//National Health Research Institutes/ ; NHRI-EX113-11133NI//National Health Research Institutes/ ; NSTC 112-2314-B-039-020-MY3//National Science and Technology Council/ ; NSTC 113-2314-B-039-045-MY3//National Science and Technology Council/ ; NSTC 114-2314-B-182A-058-MY3//National Science and Technology Council/ ; NSTC 114-2622-B-039 -001//National Science and Technology Council/ ; NSTC 114-2629-B-039-001//National Science and Technology Council/ ; MOST 109-2628-B-182A-002//Ministry of Science and Technology, Taiwan/ ; MOST 111-2314-B-182A-024-MY3//Ministry of Science and Technology, Taiwan/ ; },
abstract = {BACKGROUND: Previous studies found that sodium benzoate (the pivotal D-amino acid oxidase [DAO] inhibitor) improved cognitive function in patients with mild Alzheimer's disease (AD); however, its efficacy for mild cognitive impairment (MCI) remained inconclusive. This study aims to evaluate the efficacy and safety of sodium benzoate in treating amnestic MCI (aMCI).

METHODS: Data were pooled from three randomized, double-blind, placebo-controlled trials. One hundred thirty-three patients with aMCI were enrolled from three major medical centers in Taiwan to receive 24-week treatment of 250-1500 mg/day of sodium benzoate or placebo. The cognitive outcome was Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog), and the functional outcome was Instrumental Activities of Daily Living (IADL). Both were measured at weeks 0, 8, 16, and 24.

RESULTS: Among 133 participants, sodium benzoate therapy improved ADAS-cog scores more than placebo (P = 0.033 at week 16, 0.026 at week 24). Among 84 women, benzoate surpassed placebo in ADAS-cog (P = 0.046 at week 16, 0.029 at week 24), as well as IADL (P = 0.043 at week 24). In contrast, among 49 men, the two treatment groups did not differ significantly in both ADAS-cog and IADL scores. Both sodium benzoate and placebo were well tolerated and benzoate therapy produced no additional side effect.

CONCLUSIONS: This study is the first to demonstrate that a DAO inhibitor, sodium benzoate herein, can enhance overall cognitive function in MCI individuals. Furthermore, it can improve female patients' IADL. The finding lends support for DAO inhibition as a novel approach for early dementing processes.},
}

@article {pmid41858425,
year = {2026},
author = {Xu, M and Xiong, L and Qin, Z and Yu, X and Chen, T and Zhang, X and Jin, M and Wang, L and Cai, L and Wei, Y and Liu, H and Wang, C and Hu, H and Zou, Z},
title = {Epigenetic Changes in Alzheimer's Disease and Interventions for Therapy.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {576404},
pmid = {41858425},
issn = {1176-6328},
abstract = {With the ageing of society, the number of Alzheimer's disease (AD) patients has increased rapidly, imposing a heavy burden on families and society. This article reviews the causes of AD, particularly the epigenetic changes associated with AD, including DNA methylation, histone modifications, and noncoding RNA changes. The development of diagnostic reagents based on biomarkers specific to epigenetic changes and attempts to intervene in adverse epigenetic factor changes in AD for the treatment of AD are discussed. This review contributes to a better understanding of the relationship between epigenetics and AD and provides guidance for exploring diagnostic and therapeutic strategies.},
}

@article {pmid41858558,
year = {2026},
author = {Tran, MH and Pruitt, K and Bryarly, M and Emordi, I and Ali, A and Ma, L and Fei, B},
title = {Development and validation of a high-resolution hyperspectral imaging system for the retina.},
journal = {Journal of biomedical optics},
volume = {31},
number = {3},
pages = {036006},
pmid = {41858558},
issn = {1560-2281},
mesh = {Animals ; *Hyperspectral Imaging/methods/instrumentation ; Mice ; *Retinal Vessels/diagnostic imaging ; Algorithms ; Phantoms, Imaging ; *Retina/diagnostic imaging ; *Image Processing, Computer-Assisted/methods ; Oxygen/metabolism ; Deep Learning ; Mice, Inbred C57BL ; },
abstract = {SIGNIFICANCE: Early detection of Alzheimer's diseases, diabetic retinopathy, or macular degeneration with advanced retinal imaging technologies can help improve patient care and treatment outcome.

AIM: We aim to create a high-resolution hyperspectral imaging (HSI) system for the retina. Retinal vessel diameter and oxygenation rate will be extracted simultaneously from HSI data.

APPROACH: Our hyperspectral retinal imaging system consists of a snapshot hyperspectral camera, a high-resolution RGB camera, a beamsplitter, and an imaging endoscope. Multiple pansharpening algorithms, including deep learning methods, were developed to generate high-resolution hyperspectral images that were further used for the measurement of vessel size and oxygenation rate in mice.

RESULTS: The hyperspectral retinal imaging system was tested for its spatial resolution and spectral fidelity in retina phantoms. In vivo imaging experiments were performed in mice. The deep learning-based pansharpening algorithm achieved a root mean square error (RMSE) of 2.15 ± 0.64 , a correlation coefficient (CC) of 0.96 ± 0.05 , a spectral angle score of 0.06 ± 0.03 radians, and an error relative global dimensionless synthesis (ERGAS) score of 2.37 ± 1.71 . Oxygen saturation (sO 2) and lumen diameters of blood vessels were measured in the retina. The average lumen diameter of the venules was 45.7 ± 13.6    μ m , whereas the average lumen diameter of the arterioles was 31.5 ± 8.7    μ m . The average arteriole sO 2 was 98%, whereas the average venule sO 2 was 58%.

CONCLUSIONS: A high-resolution hyperspectral imaging system was developed and validated for retina imaging and measurement of blood vessels and oxygen saturation.},
}

Animals
*Hyperspectral Imaging/methods/instrumentation
Mice
*Retinal Vessels/diagnostic imaging
Algorithms
Phantoms, Imaging
*Retina/diagnostic imaging
*Image Processing, Computer-Assisted/methods
Oxygen/metabolism
Deep Learning
Mice, Inbred C57BL

@article {pmid41858791,
year = {2026},
author = {Su, CW and Chen, K and Wu, T and Reiman, EM and Wang, Q},
title = {TAS2R38 taster variants-linked MGAM expression in Alzheimer's disease: a novel target for precision drug repurposing.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1768436},
pmid = {41858791},
issn = {1663-4365},
abstract = {INTRODUCTION: TAS2R38 is a taste receptor gene located on human chromosome 7 that influences sensitivity to bitter tastes and has been implicated in innate immunity, glucose level, and human longevity. However, its potential association with Alzheimer's Disease (AD) has not been explored. Identifying such a genetic connection could support developing new drugs or repurposing existing ones for AD treatment.

METHODS: In this work, we examined the relationship between allele counts of TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing genetic, clinical, and biomarker data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We investigated the potential molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues across brain regions from the Religious Orders Study/Memory and Aging Project (ROSMAP). We evaluated whether FDA-approved drugs targeting the identified e-gene could reduce dementia risk using 1:1 propensity score-matched groups from longitudinal data in the National Alzheimer's Coordinating Center (NACC) study, by comparing clinical dementia progression trends between the drug-taking and non-taking groups with linear mixed-effects models.

RESULTS: Our results show that TAS2R38 supertasters were connected to a reduced AD risk with advancing age due to its association with various AD biomarkers (p < 0.001). eQTL analysis linked the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (p < 0.001). Furthermore, elevated MGAM expression correlated with more severe Tau burden (p < 0.05) and implicated in mitochondrial dysfunction in AD subjects. Notably, MGAM is a known drug target for diabetes mellitus. In NACC data, individuals taking MGAM-inhibiting drugs (acarbose and miglitol) showed slower clinical dementia rating progression (p < 0.01) in comparison with the non-taking group.

DISCUSSION: This study is the first to report a genetic association between TAS2R38 and AD biomarkers. Our findings, validated in multiple cohorts/matching groups, suggest MGAM as a novel AD drug target with existing FDA-approved inhibitors and demonstrate the potential of TAS2R38 haplotypes to inform precision drug repurposing strategies for AD, which warrants further in-depth preclinical and clinical studies.},
}

@article {pmid41858824,
year = {2026},
author = {Fu, W and Wang, K and Chen, H and Liu, T and Liu, X and Jin, Q and Tan, Z and Dong, W and Liu, W and Sang, Z},
title = {Design, synthesis and biological evaluation of novel 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives as AChE/MAO-B dual inhibitors for the treatment of Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41858824},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is an irreversible degenerative disorder of the brain, and there is no effective drug for it to date. Given its complex pathogenesis, the multi-target-directed ligand (MTDL) strategy is considered as a promising approach against AD. Herein, a series of 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives were designed and synthesized based on the MTDL strategy. The in vitro biological results indicated that 3c was a potent AChE/MAO-B dual inhibitor with an IC50 value of 0.81 μM and 0.17 μM, respectively. Molecular modeling and molecular dynamics (MD) simulations offered possible insights into the AChE/MAO-B inhibition of 3c. Moreover, 3c showed good stability and BBB permeability, as well as favorable neuroprotective effects. In vivo evaluation exhibited that 3c impressively improved the AlCl3-induced zebrafish AD model by elevating ACh, decreasing APP and inflammatory factors. Further, 3c effectively alleviated the scopolamine-induced cognitive impairment model. Therefore, 3c is a promising AChE/MAO-B dual inhibitor for treating AD.},
}

@article {pmid41860347,
year = {2026},
author = {Zhu, W and Li, H and Wang, K and Sun, M and Xiang, K and Shan, S and Ke, C},
title = {Evidence integration of acupuncture for prevention and treatment of Alzheimer's disease and mild cognitive impairment from a neuroimaging perspective.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261420235},
doi = {10.1177/13872877261420235},
pmid = {41860347},
issn = {1875-8908},
abstract = {BackgroundAcupuncture has clinical potential in treating Alzheimer's disease (AD) and mild cognitive impairment (MCI), but there is a lack of systematic review and presentation of clinical evidence from the perspective of neuroimaging in this field.ObjectiveTo conduct a systematic review of clinical studies on acupuncture for AD and MCI from the perspective of neuroimaging, and to comprehend the evidence distribution of relevant research.MethodsThis article retrieved all the neuroimaging clinical studies on acupuncture treatment for AD and MCI that were published and included in the seven databases from their establishment until February 22, 2025. It analyzed and organized the data based on the PICOS (Population, Intervention, Comparison, Outcome, Study design) principle, and presented the quality and distribution of evidence.ResultsA total of 58 studies were included. The diagnostic criteria for the research subjects mainly refer to the standards of Western medicine. The task design was mostly two-arm before-and-after comparisons and single-group immediate studies, with the intervention measures mainly including hand acupuncture and electroacupuncture. The study employed 8 neuroimaging techniques and 29 outcome measures, with a primary focus on brain functional activation regions and brain functional connectivity. Included studies had high bias risk in blinding design/implementation; overall evidence quality was acceptable.ConclusionsAcupuncture for AD and MCI demonstrates clear efficacy, which is supported by imaging evidence. In the future, more large-sample, multi-center joint clinical studies using neuroimaging methods will be needed to further investigate AD and MCI, providing more high-quality evidence-based medical evidence in this field.},
}

@article {pmid41860361,
year = {2026},
author = {Høilund-Carlsen, PF and Alavi, A and Costa, T and Neve, RL and Revheim, ME and Barrio, JR},
title = {Serious doubts about amyloid-β (Aβ) biomarkers and anti-Aβ immunotherapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261417548},
doi = {10.1177/13872877261417548},
pmid = {41860361},
issn = {1875-8908},
abstract = {Reports highlight new Alzheimer's disease treatments using anti-amyloid-β immunotherapy, but we see major concerns. The trials supporting lecanemab and donanemab approvals have methodological flaws, and the benefits may be smaller than the minimal clinically important difference-or absent-since patients with poor tolerance were excluded from efficacy analyses. Moreover, treatment increases amyloid-related imaging abnormalities, suggesting local tissue damage, and is linked to brain volume loss. These issues raise doubts about whether regulators are adequately balancing risks and benefits compared to academic critics.},
}

@article {pmid41860528,
year = {2026},
author = {Rubin, R},
title = {Lithium for Alzheimer Disease-Pilot Study Sets the Stage for Larger Trials.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.3046},
pmid = {41860528},
issn = {1538-3598},
}

@article {pmid41861574,
year = {2026},
author = {Denev, R and Berkov, S},
title = {A fast and simple method for GC-MS quantification of galanthamine in Hippeastrum papilio (Ravena) Van Sheepen and assessment of its alkaloid fractions.},
journal = {Journal of chromatography. A},
volume = {1774},
number = {},
pages = {466902},
doi = {10.1016/j.chroma.2026.466902},
pmid = {41861574},
issn = {1873-3778},
abstract = {BACKGROUND: Galanthamine, an AChE inhibitor marketed for symptomatic treatment of mild to moderate Alzheimer's disease, is produced by both chemical synthesis and extraction from plant of the Amaryllidoideae subfamily. There are a few validated GC-MS and HPLC-MS methods for its quantification in plant material. All of these methods apply multi-step sample preparation procedures including toxic solvents. The assessment of plant material and development of extraction methodologies from new plant sources (e.g. Hippeastrum papilio) requires validation of quantitative analytical methods considering the species alkaloid pattern.

RESULTS: The extraction of galanthamine from H. papilio raw material was optimized selecting 0.072% of HCl water solution as the most effective extractant. An aliquot (1 µL) of the total extract (1 mL) was directly injected into the GC-MS system avoiding any purification steps with toxic solvents. Selectivity, linearity, sensitivity, precision, accuracy, stability and robustness were determined. The LLOQ and LLOD in SIM mode were found at a concentration of 10 ng/mL and 2 ng/mL, respectively. The method was used for assessment of plant raw material, alkaloid fractions and extraction effectiveness.

SIGNIFICANCE: The method describes the fastest and simplest extraction procedure and direct aqueous injection into the GC-MS for quantification of galanthamine in plant material. As compared to the LC-MS, the use of EIMS detector provides important information and advantage in the assessment of alkaloid fractions from new plant sources of galanthamine.},
}

@article {pmid41652415,
year = {2026},
author = {Tang, F and Li, Y and Bai, X and Zhu, Z and Dong, H and Chen, J and Ye, B and Yuan, M and Wu, Q and Fu, W and Zhang, Y and Wang, C},
title = {BMAL1-GPX3 axis in the choroid plexus mitigates Aβ pathology in an amyloid mouse model.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41652415},
issn = {1742-2094},
support = {2024NSCQ-MSX0951//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; 2023NSCQ-MSX3605//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; KJQN202400476//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; KZD-JI202400406//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; 82271470//National Natural Science Foundation of China/ ; STI2030-Major Projects 2021ZD0202400//National Key Research and Development Program of China/ ; LG-GG-202401-ADA010100//Lingang Laboratory AD Special Project/ ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 (BMAL1) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of Bmal1 in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03691-9.},
}

@article {pmid41673758,
year = {2026},
author = {Zheng, D and Gu, J and Nao, J and Sun, M and Dong, X},
title = {APOE4-driven T cell dysregulation in Alzheimer's disease: single-cell genomics and Mendelian randomization reveal novel therapeutic targets.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41673758},
issn = {1742-2094},
support = {No. 2024-MS-024//Natural Science Foundation of Liaoning Province/ ; },
abstract = {UNLABELLED: The ɛ4 allele of the apolipoprotein E gene (APOE4) has been identified as a significant risk factor for late-onset AD. However, the specific genetic differences in T lymphocytes between APOE4 and APOE3 carriers are poorly understood. This study aimed to identify these important genetic distinctions and investigate the causal relationship between these differences and the risk of Alzheimer’s disease (AD), offering insights that could lead to novel treatment approaches. We sequenced single peripheral blood cells from three APOE3 and three APOE4 patients using the BD Rhapsody sequencing technology. We conducted a single-cell locus analysis, explored cell communication and signaling pathways. Finally, we selected CD8 central memory cells (CD8_CM) for differential gene, enrichment, and protein interaction analyses. Mendelian randomization (MR) analysis of expression quantitative trait loci (eQTLs) of differential genes and a genome-wide association study (GWAS) of AD were performed to verify causality and sensitivity. We selected CD8_CM as the primary target and identified 108 differentially expressed genes (DEGs). Through MR analysis, we identified nine genes with causal relationships with AD: ANXA1, BHLHE40, ATP2B4, RUNX3, CD3G, PFN1, AHNAK, C1orf21, and CAPNS1. In the replication phase, based on Wald ratios or the IVW method, the causal relationships of five genes (RUNX3, ATP2B4, C1orf21, AHNAK, and CD3G) with AD were successfully validated in another GWAS dataset. We identified the core role of CD8_CM, yielding 108 DEGs. Our integrative analysis suggests that genetically determined levels of circulating BHLHE40, ANXA1, and RUNX3, may be promising biomarkers for AD and warrant further clinical investigation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03727-0.},
}

@article {pmid41851031,
year = {2026},
author = {Sun, J and Zufiria-Gerbolés, B and Passaretti, M and Volpe, G and Mijalkov, M and Pereira, JB and , },
title = {Tracking early cognitive decline in preclinical AD with brain MRI similarity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71170},
doi = {10.1002/alz.71170},
pmid = {41851031},
issn = {1552-5279},
support = {2025-03210//Swedish Research Council/ ; FO2025-0059//Swedish Brain Foundation/ ; 2-3980/2025//Blomqvist Foundation/ ; //StratNeuro/ ; 760250/28.12.2023//Romanian Government through Romania's National Recovery Romania's National Recovery and Resilience Plan (Romanian Ministry of Research, Innovation and Digitalization under Component 9, Investment 8)/ ; PNRR-C9-I8-CF109/31.07.2023//Romanian Government through Romania's National Recovery Romania's National Recovery and Resilience Plan (Romanian Ministry of Research, Innovation and Digitalization under Component 9, Investment 8)/ ; //KID funding/ ; //KI Consolidator Grant/ ; //King Gustaf V and Queen Victoria's Foundation/ ; //Gamla Tjänarinnor/ ; //Gun och Bertil Stohnes Stiftelse/ ; //Dementia Foundation/ ; //Lars Hierta Memorial Foundation/ ; AF-1032782//Alzheimer Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Magnetic Resonance Imaging ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Male ; Female ; *Brain/pathology/diagnostic imaging ; Aged ; Biomarkers/cerebrospinal fluid ; Neuroimaging ; Prodromal Symptoms ; Aged, 80 and over ; Amyloid beta-Peptides/cerebrospinal fluid ; Early Diagnosis ; Disease Progression ; },
abstract = {INTRODUCTION: Early detection of neuroanatomical changes in preclinical Alzheimer's disease (AD) is critical for timely intervention. However, conventional magnetic resonance imaging (MRI) and fluid biomarkers often lack sensitivity to subtle structural alterations in early disease stages.

METHODS: To identify early brain alterations, we applied a perturbation-based brain similarity approach to cognitively normal participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS), stratified by amyloid status. We evaluated its predictive performance for cognition and diagnostic conversion against cortical thickness, volumetric MRI, and fluid biomarkers.

RESULTS: In both cohorts, brain similarity consistently outperformed other biomarkers across cognitive domains and amyloid groups. It also achieved superior accuracy in predicting clinical conversion and exhibited associations with cytoarchitectural organization.

DISCUSSION: These findings highlight brain similarity as a sensitive marker of early neuroanatomical disruption in AD. Its ability to detect subtle structural changes before overt atrophy underscores its potential for early disease monitoring and treatment assessment in preclinical AD trials.

HIGHLIGHTS: Brain similarity captures early brain changes in preclinical Alzheimer's disease (AD). Brain similarity outperforms conventional biomarkers such as cortical thickness, volume measures, and fluid biomarkers in predicting cognitive decline. Brain similarity predicts conversion to mild cognitive impairment and AD more accurately than traditional imaging markers, and its predictive performance is further improved when combined with fluid biomarkers. Brain similarity captures structural disruptions associated with cortical layer II of the cytoarchitectonic lamina of human neocortex.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Magnetic Resonance Imaging
*Cognitive Dysfunction/diagnostic imaging/pathology
Male
Female
*Brain/pathology/diagnostic imaging
Aged
Biomarkers/cerebrospinal fluid
Neuroimaging
Prodromal Symptoms
Aged, 80 and over
Amyloid beta-Peptides/cerebrospinal fluid
Early Diagnosis
Disease Progression

@article {pmid41851960,
year = {2026},
author = {Bhoopal, B and Gollapelli, KK and Damuka, N and Krizan, I and Miller, M and Fitzgerald, RW and Amesar, N and Mumbaraddi, D and Zhu, D and Cervera-Juanes, R and Jadiya, P and Whitlow, CT and Solingapuram Sai, KK},
title = {Synthesis, Radiochemistry, and Preclinical Assessment of the First GPR39 PET Imaging Agent.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c03351},
pmid = {41851960},
issn = {1520-4804},
abstract = {GPR39 is a zinc-sensing G protein-coupled receptor with critical roles in neurophysiological and metabolic processes across brain, pancreas, gut, liver, and fat tissues. Activated by extracellular zinc ions, GPR39 is involved in neurodegenerative diseases including altered levels in Alzheimer's disease (AD). Quantifying GPR39 levels in vivo could significantly advance understanding of its role in various metabolic and disease processes, enabling drug development and treatment monitoring. Our study reports the synthesis, radiolabeling, and comprehensive preclinical evaluation of the first radiotracer for GPR39 imaging: [[11]C]TMN-OMe. The radiotracer demonstrated high radiochemical purity, molar activity, and stability in human serum. In vivo microPET/CT imaging, biodistribution, and autoradiography analyses confirmed selective binding to GPR39, with significantly reduced brain uptake in GPR39 knockout and AD mice, and in blockade conditions. Collectively, these findings support using [[11]C]TMN-OMe to quantify GPR39 levels in vivo and define GPR39-based imaging as a novel platform to study mechanistic changes in neurological disorders.},
}

@article {pmid41852095,
year = {2026},
author = {Zecca, V and Palombelli, G and Vanacore, N and Canese, R},
title = {The Role of Magnetic Resonance Spectroscopy (MRS), Diffusion-Tensor-Imaging (DTI) and Structural MRI in the Alzheimer's Disease and Mild Cognitive Impairment Diagnosis: A Review.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70296},
pmid = {41852095},
issn = {1522-2586},
abstract = {Alzheimer's disease (AD) is one of the most common neurological disorders affecting older adults, with approximately 7.2 million cases only in the United States. This number is projected to increase to 13.8 million in the United States by 2060, leading to increased expenditures for healthcare, long-term care and hospice services. Consequently, great emphasis is placed on prevention and the development of early diagnosis techniques, which can lead to timely treatment and the prevention of the consequences of full-blown disease. In this review, we analyze the potential diagnostic value of biomarkers derived from a multimodal approach based on magnetic resonance spectroscopy, diffusion tensor imaging, and magnetic resonance imaging, capable of detecting metabolic, microstructural, and anatomical changes, respectively, that precede the cognitive and behavioral changes observed in AD by years. The primary aim is to evaluate whether the combined and complementary use of these methods can identify early biomarkers useful for recognizing AD in its early stages, predicting progression from MCI to AD, supporting patient stratification, and monitoring cognitive decline or response to treatment. We identified regions more susceptible to metabolic alterations (PCC and hippocampus) and trajectories of structural brain alterations (atrophy or diffusivity abnormalities). The assessment of such imaging biomarkers may serve as the foundation for future prospective studies aimed at developing differential diagnostic methods, a crucial goal within the broader context of dementias, by adopting standardized multimodal MRI protocols. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 1.},
}

@article {pmid41852131,
year = {2026},
author = {Jin, MX and Qiu, JY and Jiang, HY},
title = {Marine-Derived Chitosan Oligosaccharides and Their Derivatives: A New Hope for Alzheimer's Prevention and Treatment - A Critical Review.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {3},
pages = {e02777},
doi = {10.1002/cbdv.202502777},
pmid = {41852131},
issn = {1612-1880},
support = {81760207//National Natural Science Foundation project/ ; 2024AY10021//Jiaxing Municipal Public Welfare Research Program Project/ ; },
mesh = {*Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Chitosan/chemistry/pharmacology/therapeutic use ; Humans ; *Oligosaccharides/chemistry/pharmacology/therapeutic use ; Animals ; *Aquatic Organisms/chemistry ; Antioxidants/chemistry/pharmacology ; *Neuroprotective Agents/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive degenerative disease of the central nervous system. Its clinical manifestations are mainly cognitive and memory disorders, and its incidence rate and mortality are increasing year by year. Chitosan oligosaccharides (COS), also known as β-1,4-oligoglucosamine, are natural alkaline polysaccharides and the only positively charged ones in nature. Due to its low molecular weight, good water solubility, and excellent biocompatibility, non-toxicity, and biodegradability, in recent years, it has received increasing attention from domestic and foreign researchers and enterprises. COS is of great significance in the prevention and treatment of AD; the main mechanisms of action include inhibiting acetylcholinesterase and beta-secretase activity, preventing abnormal phosphorylation of tau protein, chelating copper ions, protecting neuronal cells, and exhibiting antioxidant effects. This review primarily combines the latest research results, both domestic and international, to summarize and analyze the anti-AD effects and possible mechanisms of COS, aiming to provide the theoretical basis and the reference for the in-depth study of COS in the fields of biomedicine and functional foods and for its wider application in the fields of medicine and health food.},
}

*Alzheimer Disease/drug therapy/prevention & control/metabolism
*Chitosan/chemistry/pharmacology/therapeutic use
Humans
*Oligosaccharides/chemistry/pharmacology/therapeutic use
Animals
*Aquatic Organisms/chemistry
Antioxidants/chemistry/pharmacology
*Neuroprotective Agents/chemistry/pharmacology
Acetylcholinesterase/metabolism

@article {pmid41852627,
year = {2026},
author = {Toledano-Pinedo, M and Iriepa, I and Rodríguez-Fernández, MM and Marco-Contelles, J},
title = {Masupirdine, a Selective Serotonin 5‑HT6 Receptor Antagonist for Alzheimer's Disease.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {3},
pages = {761-763},
pmid = {41852627},
issn = {2575-9108},
abstract = {Masupirdine is an oral, small, and safe molecule, readily available by a robust, two-step synthetic scheme, showing a potent, selective serotonin 5-HT6 receptor antagonist profile, pro-cognitive effects in various behavioral animal models in Phase 3 clinical trials for the treatment of agitation in patients with Alzheimer's dementia.},
}

@article {pmid41853003,
year = {2026},
author = {Khushi, P and Parmar, NJ and Daga, R and Sethumadhavan, J and Kale, PK and Laddha, R},
title = {Neuroprotectants: The Next Frontier in Neurology.},
journal = {Journal of pharmacy & bioallied sciences},
volume = {18},
number = {Suppl 1},
pages = {S1-S3},
pmid = {41853003},
issn = {0976-4879},
abstract = {Neuroprotectants are drugs or substances that help protect the brain and nerves from damage caused by injuries or diseases like stroke, Alzheimer's disease, and Parkinson's disease. This review looks at different types of neuroprotective agents, including those that reduce inflammation, prevent cell death, or improve blood flow to the brain. While many of these substances show good results in lab studies, only a few have been successful in human trials. This is often due to problems like delayed treatment, difficulty reaching the brain, and differences between patients. The review also discusses future clinical trials and how new technologies and targeted treatments may improve outcomes. Understanding how these agents work and how to test them better could lead to more effective treatments for brain disorders.},
}

@article {pmid41853217,
year = {2026},
author = {Karthikeyan, A and Gopinath, N and Krishna, N and Joseph, A and Krishnamurthy, RG and Nair, BG},
title = {Neuroprotective potential of a novel marine metabolite from S. rhizophila BGNAK1 targeting acetylcholinesterase in Alzheimer's disease.},
journal = {3 Biotech},
volume = {16},
number = {4},
pages = {143},
pmid = {41853217},
issn = {2190-572X},
abstract = {UNLABELLED: Secondary metabolites from the marine bacterium Stenotrophomonas rhizophila strain BGNAK1 were evaluated for neuroprotective activity using biochemical and cellular assays relevant to Alzheimer's disease. The crude extract exhibited significant acetylcholinesterase (AChE) inhibitory activity with an IC50 value of 106.0163 µg/mL, indicating effective modulation of cholinergic function. Antioxidant evaluation revealed strong free radical scavenging capacity, with DPPH radical inhibition of and 97% at 1.0 mg/ml. The extract also significantly reduced intracellular reactive oxygen species levels, showing a reduction compared to untreated control cells at the highest tested concentration. Cytotoxicity analysis using PC12 and SH-SY5Y neuroblastoma cell lines demonstrated > 85% cell viability across all tested concentrations, confirming good biocompatibility. No significant morphological alterations or growth inhibition were observed under treatment conditions. Overall, these results demonstrate that metabolites derived from S. rhizophila BGNAK1 exert multi-target neuroprotective effects through combined cholinesterase inhibition and antioxidant mechanisms. Although direct neuronal injury models were not employed, the integrated biochemical and cellular findings provide quantitative evidence supporting the neurotherapeutic potential of marine bacterial metabolites and justify further investigation into their role in Alzheimer's disease-oriented drug discovery.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04751-w.},
}

@article {pmid41853467,
year = {2026},
author = {Teipel, S and Grazia, A and Peters, O and Priller, J and Schneider, A and Wiltfang, J and Bartels, C and Schott, BH and Jessen, F and Duezel, E and Yakupov, R and Buerger, K and Perneczky, R and Laske, C and Spottke, A and Wagner, M and Peltner, J and Kilimann, I and Haenisch, B},
title = {Associations of anticholinergic burden of medication with cognitive decline and longitudinal brain atrophy in the Alzheimer's disease spectrum.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1751326},
pmid = {41853467},
issn = {1663-4365},
abstract = {BACKGROUND: Anticholinergic side effects of pharmacological treatment are a risk factor for cognitive decline in older people. Here, we aimed to assess the effect of anticholinergic burden of treatment on longitudinal rates of cognitive change and atrophy in functionally related brain regions in people from the Alzheimer's disease (AD) spectrum.

METHODS: We determined associations of anticholinergic burden of pharmacological treatment with rates of global cognition, episodic memory and executive function decline as well as basal forebrain and hippocampus atrophy in participants of the memory clinic based DELCODE cohort, spanning the range from cognitively normal through subjective cognitive decline, mild cognitive impairment and AD dementia. We had 794 cases with neuropsychological outcomes, and a subset of 703 cases with MRI outcomes. Effects were assessed using mixed effect models in a Bayesian framework using prior-insensitive cross-validated Bayes factors (CV-BF) and parameter estimates.

RESULTS: We found moderate evidence for an association of anticholinergic burden with baseline levels of cognitive impairment for the PACC5 as a global cognitive function score (CV-BF = 9.0) with more impairments with higher burden, but not with basal forebrain and hippocampus volumes, and weak evidence for an association of anticholinergic burden with longitudinal rates of change in the trail-making test B as an executive function score (CV-BF = 2.5), but not for other cognitive scores and not for brain volumes.

CONCLUSION: In the presence of prodromal or manifest AD, in a memory clinic-based cohort anticholinergic burden had only a modest effect on cognitive decline and no effect on atrophy in brain regions that are related to the cholinergic system.},
}

@article {pmid41853851,
year = {2026},
author = {Jun, JE and Kim, S and Jeong, IK and Kim, JH},
title = {Dementia Risk in Type 1 and 2 Diabetes: A Nationwide Population-Based Comparison.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70677},
pmid = {41853851},
issn = {1463-1326},
abstract = {AIMS: Diabetes is increasingly recognised as a major contributor to cognitive decline and dementia, but the risk varies by diabetes type and treatment intensity. We compared the risk of all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD) among individuals with and without diabetes.

METHODS: This population-based retrospective cohort study analysed data from the Korean National Health Insurance Service (2013-2024). A total of 1 322 651 adults aged ≥ 40 years without prior dementia were included. Participants were classified as non-diabetic, type 2 diabetes (T2DM) with oral hypoglycemic agents (OHAs), T2DM with insulin, or type 1 diabetes (T1DM). Incident dementia was identified using ICD-10 codes and anti-dementia prescriptions. Multivariable Cox proportional hazards models adjusted for demographic, lifestyle and clinical factors estimated adjusted hazard ratios (aHRs) for dementia.

RESULTS: Dementia incidence rates per 1000 person-years were 4.3 (non-diabetic), 12.7 (T2DM with OHA), 17.9 (T2DM with insulin) and 21.1 (T1DM). Compared with non-diabetic participants, aHRs for all-cause dementia were 1.29 (95% CI 1.26-1.32) for T2DM with OHA, 2.14 (2.00-2.28) for T2DM with insulin and 2.35 (2.12-2.59) for T1DM. Similar trends were observed for AD and VaD. Dementia risk was highest in individuals with T1DM and insulin-treated T2DM, with no significant difference between these groups.

CONCLUSIONS: Diabetes was associated with a higher risk of dementia, particularly among individuals with T1DM and insulin-treated T2DM, suggesting that insulin-requiring diabetes represents a high-risk phenotype for cognitive decline. Proactive cognitive screening and optimised glycemic management, including strategies to reduce glycemic variability such as continuous glucose monitoring, may help mitigate dementia risk in these vulnerable populations.},
}

@article {pmid41854365,
year = {2026},
author = {Oliveira, LM and Frasier, M and Hutten, SJ},
title = {Collaborative action for biomarker breakthroughs: Validating α-synuclein seed amplification assays in Parkinson's disease.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261431949},
doi = {10.1177/1877718X261431949},
pmid = {41854365},
issn = {1877-718X},
abstract = {The alpha-synuclein seed amplification assay in cerebrospinal fluid is the first validated molecular measurement of alpha-synuclein biology in a living person. The SAA test is transforming our understanding of aging and neurodegenerative diseases by detecting abnormal synuclein biology, and data suggests SAA positivity can occur across Parkinson's disease, Alzheimer's disease, and Dementia with Lewy Bodies. To accelerate development of this important research tool, the Michael J. Fox Foundation proactively funded a community of researchers to work both independently and collaboratively, leading to rapid and iterative progress and validation. The collective validation of the assay across industry and academic groups culminated in a Food and Drug Administration Letter of Support for the test in clinical trials for PD. This article describes the principles that accelerated the development of the assay including patient engagement, collaboration, a commitment to open science through data, sample, and knowledge sharing, and showcases how an international community of experts rallied together towards a common goal.},
}

@article {pmid41854733,
year = {2026},
author = {Liu, K and Zhang, XY and Wang, YT and Wang, R and Jin, RH and Bing, YH},
title = {Therapeutic Potential of Somatostatin and Its Analogues in Alzheimer's Disease: From Molecular Mechanisms to Preclinical Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41854733},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Somatostatin/analogs & derivatives/therapeutic use/pharmacology ; Animals ; Drug Evaluation, Preclinical ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Currently approved agents, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, provide only modest symptomatic benefit without modifying disease progression. Increasing evidence highlights the somatostatin (SST) system and its analogues (SSAs) as potential multitarget therapies. Somatostatin receptors (SSTR1-5) are widely expressed in cognition-related brain regions and participate in amyloid-β metabolism, tau phosphorylation, neuroinflammation, and synaptic plasticity. Preclinical studies suggest that SSAs enhance amyloid clearance via neprilysin activation, attenuate tau pathology through PI3K/Akt signaling, regulate APOE4 expression, and modulate microglial function, thereby protecting synaptic integrity. Compared with current monotherapies, SSAs may provide broader therapeutic benefits, particularly if applied in prodromal or early stages of AD. Advances in delivery strategies, including peptide modification, nanocarrier-based transport, and physically assisted blood-brain barrier (BBB) penetration, further improve translational potential. However, challenges such as poor BBB permeability, incomplete mechanistic understanding, and limited clinical data remain. Integration of systems biology, biomarker-driven precision medicine, and novel delivery technologies may facilitate the development of SSA-based interventions as complementary strategies for AD management.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Somatostatin/analogs & derivatives/therapeutic use/pharmacology
Animals
Drug Evaluation, Preclinical
Amyloid beta-Peptides/metabolism
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41855773,
year = {2026},
author = {Ouk, K and Fernández-Klett, F and Schormann, E and Greiner, A and Santaella, A and Fernández-Zapata, C and Böttcher, C and Krüger, E and Priller, J},
title = {Rapamycin treatment reduces CD11c[+] microglia and increases amyloid plaque load in 5xFAD mice.},
journal = {Experimental neurology},
volume = {401},
number = {},
pages = {115709},
doi = {10.1016/j.expneurol.2026.115709},
pmid = {41855773},
issn = {1090-2430},
abstract = {The mammalian target of rapamycin (mTOR) is involved in immune regulation and in the metabolism of β-amyloid (Aβ) and tau peptides in Alzheimer's disease (AD). In this study, we investigated the effects of the mTOR inhibitor, rapamycin, on central and peripheral immune profiles, proteasome activity, Aβ pathology, and spontaneous exploratory activity and place recognition in the 5xFAD mouse model of amyloid pathology. Using flow cytometry, we found that rapamycin induced changes in immune cell numbers and phenotypes in 5xFAD mice, notably a significant decrease of CD11c[+] microglia in cortex and hippocampus of 5xFAD mice. This was associated with increased Aβ plaque load. Concomitantly, we observed a decrease in immunoproteasome content and activity. In peripheral blood, rapamycin treatment resulted in higher percentages of granulocytes, whereas splenic T lymphocytes were reduced. No changes in the open field and modified Y-maze tests were observed following rapamycin treatment in wild-type and 5xFAD mice. Our results reveal detrimental effects of rapamycin on amyloid plaque accumulation and CD11c[+] disease-associated microglial subsets in cortex and hippocampus of 5xFAD mice, which is an important finding given two ongoing phase 2 clinical studies of rapamycin treatment in AD.},
}

@article {pmid41856031,
year = {2026},
author = {Wang, X and Wang, X and Zhao, H and Zhao, C and Wang, P and Song, T},
title = {A compound pulsed magnetic field achieves superior cognitive benefits against Alzheimer's disease progression via multi-level restoration of neural oscillations and cerebral perfusion.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {2},
pages = {e00887},
doi = {10.1016/j.neurot.2026.e00887},
pmid = {41856031},
issn = {1878-7479},
abstract = {The link between impaired gamma oscillations and Alzheimer's disease (AD) has inspired therapies using rhythmic physical stimuli. However, given that cognition requires cross-frequency interactions like theta-gamma coupling, single-frequency stimulation may yield limited benefits. This study therefore applied a compound pulsed magnetic field (cPMF) with theta rhythm-modulated gamma frequency to evaluate its efficacy and mechanisms against AD pathology compared with single gamma-frequency pulsed magnetic field (sPMF). Local field potential results showed that cPMF outperformed sPMF by significantly enhancing hippocampal oscillations and particularly rescuing the impaired theta-gamma phase-amplitude coupling in AD mice, which was positively correlated with improved cognitive performance in behavioral tests. Correspondingly, cPMF treatment enhanced blood flow perfusion in the prefrontal and cerebral cortices of AD mice, which may contribute to amyloid-β clearance and neuroinflammation attenuation. At the molecular level, cPMF rescued AD-related transcriptional alterations by upregulating key genes involved in cholinergic signaling (Chat, Chrm1), glymphatic function (Aqp4), and synaptic plasticity (Gria1, an AMPA receptor subunit). These findings indicated that cPMF stimulation achieved multi-level restorative effects by enhancing neuronal activity, promoting cerebral perfusion, facilitating amyloid-β clearance, and rectifying aberrant gene expression, ultimately leading to cognitive improvement in AD mice. This cPMF stimulation paradigm highlights the therapeutic potential of targeting endogenous oscillatory interactions for treating neurological disorders.},
}

@article {pmid41844465,
year = {2026},
author = {Liu, J and Cao, F and Li, Z and Zeng, H and Zhou, M and He, Q and Jiang, W and Li, Y and Yan, J},
title = {Association between exogenous hormone use and dementia: A prospective cohort study and synthetic analysis.},
journal = {Maturitas},
volume = {208},
number = {},
pages = {108895},
doi = {10.1016/j.maturitas.2026.108895},
pmid = {41844465},
issn = {1873-4111},
abstract = {OBJECTIVES: To investigate the controversial association between exogenous hormone use (EHU) and dementia, with a focus on subtype-specific risks.

STUDY DESIGN: This prospective cohort study followed 273,069 women in the UK Biobank over 3,802,608 person-years, identifying 4,710 dementia cases.

MAIN OUTCOME MEASURES: Cox models assessed use of oral contraceptive (OC) and hormone replacement therapy (HRT) in relation to all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) across treatment durations. Subgroup analyses were stratified by age, ethnicity, APOE status, education, income, and reproductive factors. A systematic review was conducted to synthesize existing evidence.

RESULTS: In the cohort study, OC use was associated with reduced risks of all-cause dementia (HR 0.90, 95%CI 0.84-0.95), AD (HR 0.87, 95%CI 0.79-0.95), and VaD (HR 0.81, 95%CI 0.70-0.93), particularly after 4-14 years of use. HRT showed no significant association with increased dementia risk. Synthesized results largely corroborated these findings: OC use was associated with reduced risks of dementia (HR 0.90, 95%CI 0.89-0.92); and although four European studies reported a moderately increased AD risk after post-menopausal HRT use, neither cohort-based studies (HR 0.98, 95%CI 0.90-1.06) nor traditional case-control studies (OR 1.00, 95%CI 0.90-1.11) found an association between HRT and dementia.

CONCLUSIONS: Our combined evidence does not support an increased risk of dementia associated with OC use; similarly, no clear association was observed between HRT and increased dementia risk. Clinical decisions on EHU should be individualized, balancing overall benefits against potential risks.},
}

@article {pmid41844585,
year = {2026},
author = {Yang, M and Tong, L and Guo, Z and Tan, Z and Holmes, TC and Yu, Z and Xu, X},
title = {Evaluating the potential of acupuncture for Alzheimer's disease treatment: A meta-analysis and systematic review of mouse model studies.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03923-9},
pmid = {41844585},
issn = {2158-3188},
abstract = {Acupuncture is an ancient practice that was developed within the framework of traditional Chinese medicine. While acupuncture has been recently proposed as a therapy for Alzheimer's disease (AD), acupuncture effects are not well understood in terms of neural mechanisms. Here, we review and examine the studies that used AD mouse models and analyze the experiments where researchers administered electroacupuncture (EA) to AD mice to assess the potential therapeutic impact of acupuncture on disease pathology and cognitive function in controlled laboratory settings. We analyzed 29 relevant PubMed articles published between January 2014 and July 2025. Our results reveal that EA significantly reduces both amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels and neuroinflammatory biomarkers, including molecular signatures for activated microglia and astrocytes in the brain. EA also enhances cognitive functions. While no study directly compared acupoint strategies, the indirect comparisons in our network analysis suggest that GV20 has potential as a therapeutic target for AD. Our present meta-analysis and review of literature add to the evidence of integrative health practices for acupuncture-based Alzheimer's disease treatment.},
}

@article {pmid41845487,
year = {2026},
author = {Wu, J and Ge, Y and Zhang, L and Huang, J and Huang, N and Luo, Y},
title = {Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway.},
journal = {Stem cell research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13287-026-04954-1},
pmid = {41845487},
issn = {1757-6512},
support = {ZK [2024]-680//Science and Technology Department of Guizhou Province/ ; ZK [2021]-570//Science and Technology Department of Guizhou Province/ ; 82160858//National Natural Science Foundation of China/ ; HZ-2022-45, [2024] No. 6, HZ-2025-06//Zunyi Science and Technology Bureau/ ; ZSYS(2025)040//Guizhou Provincial Science and Technology Department/ ; },
abstract = {Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer's disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.},
}